Compounds that interact with kinases

ABSTRACT

A method of inhibiting or effecting the activity of protein kinase activity which comprises contacting a protein kinase with a compound of formula (I) being a derivative of a furanose or pyranose form of a monosaccharide, or a pharmaceutically acceptable salt thereof.

FIELD OF THE INVENTION

The invention is directed to classes of biologically active compoundsthat interact in a pharmaceutically significant manner with proteinkinases, and particularly to provide compounds suitable for thetreatment of disorders mediated by protein kinase activity. Theinvention is also directed to treatment of the above mentioneddisorders. The invention is also directed to the preparation of novelcompounds per se.

BACKGROUND OF THE INVENTION

The drug discovery landscape has been transformed by the genomicsrevolution. Advances in the understanding of biomolecular pathways andthe roles they play in disease is generating vast numbers of targets fortherapeutic intervention. Protein kinases now represent an extensive andimportant class of therapeutic targets.

Kinases are key components in almost all signal transduction pathways,modulating extracellular and intracellular signalling processes thatmediate events such as cell growth and differentiation, metabolism andapoptosis. Kinases do this by catalysing the transfer of a phosphategroup from ATP to protein substrates. The pivotal role of kinases isemphasized by the fact that kinases represent the third most populousdomain in the proteome.

Kinases have been implicated in many diseases. Twenty percent ofoncogenes code for tyrosine kinases. Kinases play pivotal roles in manyleukemias, tumours and other proliferative disorders. Other statesinvolving kinases include inflammatory disorders such as psoriasis,cardiovascular diseases such as restenosis, viral induced diseases suchas Kaposi's sarcoma, circulatory diseases such as atherosclerosis andfibroproliferative diseases. Specific kinases are often implicated inparticular disease states and therefore present themselves as potentialtargets for therapeutic intervention.

The kinase family includes serine/threonine kinases and tyrosinekinases, with the amino acid referring to the particular residue on aprotein substrate that is phosphorylated. The tyrosine kinases can befurther divided into receptor tyrosine kinases and non-receptor tyrosinekinases.

Considering the rate of generation and nature of the targets currentlybeing deconvoluted by biologists, there is a need for the development ofdrug candidates, designed in a rational manner to purposely interactwith selected targets, such as the kinases.

From a drug discovery perspective, carbohydrate pyranose and furanoserings and their derivatives are well suited as templates. Each sugarrepresents a three-dimensional scaffold to which a variety ofsubstituents can be attached, usually via a scaffold hydroxyl group,although occasionally a scaffold carboxyl or amino group may be presentfor substitution. By varying the substituents, their relative positionon the sugar scaffold, and the type of sugar to which the substituentsare coupled, numerous highly diverse structures are obtainable. Animportant feature to note with carbohydrates, is that moleculardiversity is achieved not only in the type of substituents, but also inthe three dimensional presentation. The different stereoisomers ofcarbohydrates that occur naturally, offer the inherent structuraladvantage of providing alternative presentation of substituents. We havedeveloped a system that allows the chemical synthesis of highlystructurally and functionally diverse derivatised carbohydrate andtetrahydropyran structures, of both natural and unnatural origin. Thediversity accessible is particularly augmented by the juxtaposition ofboth structural and functional aspects of the molecules.

A number of kinase inhibitors have appeared in the scientific literatureto date. Many have entered human clinical trials and in two cases,Gleevac and Iressa, approval for the treatment of various tumours hasbeen granted (Cohen, P., Nature Tev. Drug Discovery, 1, 309-316, 2002).The specificity of published kinase inhibitors varies widely and it isapparent from the study of Gleevac that specificity for a single kinaseis not a prerequisite for the inhibitor becoming a useful drug, indeedthe inhibition of more than one kinase may be an advantage fortherapeutic intervention. Despite some promiscuity in the target kinasebeing acceptable, it is generally considered desirable to have goodselectivity for the target kinase(s) over more general “housekeeping”kinases. Thus selectivity and inhibitor potency must be assessed on acase by case basis.

The level of inhibition in cell based assays also shows considerablevariation from approximately 0.1 micromolar to over 100 micromolar asexemplified by the following table (a more detailed study can be foundin: Davies et. al., Biochem. J., 351, 95-105, 2000; and Bain et. al.,Biochem. J., 371, 199-204, 2003). It is frequently the case that themost potent inhibitor is not the most suitable inhibitor for therapeuticpurposes.

Inhibitor concen- Top 5 kinases inhibited kinase tration and residualactivity ML-9 MSK-1 ROCK-II SmMLCK S6K1 CDK2 100 μM  14%  23% 25% 27%38% LY PI3K CK2 PHK GSK3β SGK 294002 13%  18% 44% 53% 72% 50 μM HA1077ROCK-II PRK2 MSK1 S6K1 PKA 20 μM 7% 15% 19% 32% 35% PP2 LCK CDK2 CK1SAPK2a MKK1 10 μM 1%  3%  6% 21% 55% Ro-31- MAPKAPK1b MSK1 PKCα GSK3βS6K1 8220 2%  2%  3%  5%  6%  1 μM MSK-1 = mitogen and stress activatedprotein kinase 1; ROCK-II = Rho associated coiled coil forming proteinkinase II; SmMLCK = smooth myosin light chain kinase; S6K1 = p70 S6kinase; CDK2 = cyclin dependant kinase 2; PI3K = phosphoinositide 3kinase; CK2 = casein kinase 2; PHK = phosphorylase kinase; GSK3β =glycogen synthetase kinase 3β; SGK = serum and glucocortin inducedkinase; PRK2 = PKC related kinase 2; PKA = protein kinase A; LCK = Tcell specific kinase; CK1 = casien kinase 1; SAPK2a = p38 kinase; MKK1 =mitogen activated protein kinase 1; MAPKAP-K1b = mitogen activatedprotein kinase activated protein kinase 1b; PKCα = protein kinase Calpha.It will be clearly understood that, if a prior art publication isreferred to herein, this reference does not constitute an admission thatthe publication forms part of the common general knowledge in the art inAustralia or in any other country.

SUMMARY OF THE INVENTION

Using the axioms of this drug discovery methodology, we synthesisedseveral novel classes of chemotypes in an effort to develop drugcandidates against kinase targets.

Kinases selected examples from the three different classes;serine/threonin kinase, tyrosine receptor kinase and tyrosinenon-receptor kinase have been explored to determine the generality ofthe current invention. Compounds were tested within the industrystandard concentration range described above and have revealed potentand selective inhibitors against each selected kinase target.

It is a general object of the invention to provide compounds suitablefor the treatment of disorders mediated by protein kinase activity andin the treatment of the above mentioned disorders.

It is an optional object of the invention to provide a pharmaceuticalformulation comprising at least one compound as described herein or apharmaceutically acceptable salt thereof, together with one or morepharmaceutically acceptable carriers, diluents or excipients.

It is a further optional object of the invention to provide a method oftreatment of a human or animal subject suffering from a disordermediated by aberrant protein kinase activity which method comprisesadministering to the human or animal subject an effective amount of acompound as described herein or a pharmaceutically acceptable saltthereof.

It is a further object of the invention to prepare novel compounds perse

In one form, the invention comprises method of inhibiting or effectingprotein kinase activity which comprises contacting a protein kinase witha compound of formula I being a derivative of a furanose or pyranoseform of a monosaccharide, or a pharmaceutically acceptable derivativethereof

-   -   Wherein;    -   n is 1 or 2,    -   X is selected from the group consisting of: OR1, an        unsubstituted 5 or 6 membered heterocyclic moiety, a substituted        5 or 6 membered heterocyclic moiety, an unsubstituted 9 or 10        membered heterobicyclic moiety and a substituted 9 or 10        membered heterobicyclic moiety,    -   R1 is selected from the group consisting of: C1 to C7 alkyl, C1        to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14        aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14        heteroarylalkyl,    -   Y is selected from the group consisting of: an unsubstituted 5        or 6 membered heterocyclic moiety; a substituted 5 or 6 membered        heterocyclic moiety, an unsubstituted 9 or 10 membered        heterobicyclic moiety and a substituted 9 or 10 membered        heterobicyclic moiety; an amino acid, a dipeptide, and

-   -   R6 is selected from the group consisting of: H, C1 to C7 alkyl,        C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to        C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl or C3 to C14        heteroarylalkyl,    -   with the proviso that R6, R7 and R8 are not all H,    -   R9 is selected from H, or —(CO)—R6,    -   R7, R8, R11, R12, R14, are independently selected from the group        consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7        alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6        to C14 arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl,        C6 to C14 arylalkyl and C6 to C14 heteroarylalkyl,    -   R13 is selected from the group consisting of: unsubstituted        phenyl unsubstituted benzyl, substituted phenyl, substituted        benzyl, H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl,        C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14        arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to        C14 arylalkyl or C6 to C14 heteroarylalkyl, —S—R6 and —O—R6,    -   R15 is absent or is at least one substituent on the aromatic        ring which are independently selected from the group consisting        of: OH, NO, NO₂, NH₂, N₃, halogen, CF₃, CHF₂, CH₂F, nitrile,        alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid,        carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl,        heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl,        aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted        imine, sulfate, sulfonamide, phosphate, phosphoramide,        hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, alkyl,        aminoaryl, aminoheteroaryl, thioalkyl, thioaryl and        thioheteroaryl.        R1 may be substituted, cyclic or acyclic, branched and/or        linear.        R7 and R8 may combine to form a cyclic structure.        R6 and one of R7 or R8 may combine to form a cyclic structure.        R11 and R12 may combine to form a cyclic structure,        X may be selected from: OR1,

-   -   R1 and R3 are independently selected from the group consisting        of: C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7        heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14        arylalkyl and C3 to C14 heteroarylalkyl,    -   R4 is selected from the group consisting of: H, C1 to C7 alkyl,        C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to        C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to        C14 heteroarylalkyl,    -   R5 is selected from the group consisting of: H, C1 to C7 alkyl,        C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to        C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl or C3 to C14        heteroarylalkyl, C1 to C7 acyl, C6 to C14 arylacyl, and C3 to        C14 heteroarylacyl,    -   R2 is selected from the group consisting of: —(C═O)—R3,        —(C═O)—OR4, and —(C═O)—NH—R4,    -   Y is selected from:

At least one of R1-R14 may be substituted and these substituents and thesubstituents on the substituted 5 or 6 membered heterocyclic moiety andthe substituted 9 or 10 membered heterobicyclic moiety may be selectedfrom the group consisting of: OH, NO, NO₂, NH₂, N₃, halogen, CF₃, CHF₂,CH₂F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid,carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl,heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl,aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate,sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate,hydroxamic acid, heteroaryloxy, aminoalkyl, alkyl, aminoheteroaryl,thioalkyl, thioaryl or thioheteroaryl, which may optionally be furthersubstituted.

X may comprise

X may comprise

X may comprise —OR1Y may comprise A as described above.Y may comprise B as described above.Y may comprise C as described above.Y may comprise D as described above.Y may comprise E as described above.Y may describe F as described above.Y may comprise G as described above.

The protein kinase may comprise a serine or threonine kinase.

The protein kinase may comprise a tyrosine kinase.

The protein kinase may comprise one or more of the isoforms of proteinkinase C.

The protein kinase may comprise Tie-2, also known as TEK, HPK-6, TIE-2VMCM, VMCM1.

The protein kinase may comprise c-Kit also known as SCFR, CD117, PBT.

The protein kinase may comprise VEGF-R2/KDR also known as VEGFR2,VEGFR-2, VEGFR, Hs.KDR, Hs.12337, FLK1, FLK-1.

The protein kinase may comprise EGF-R also known as ERBB1, ERBB,EGFRvIII.

The protein kinase may comprise Abl also known as c-ab1, c-ABL, JTK7,p150, ABL1.

The protein kinase may comprise MET also known as HGFR, C-MET, RCCP2.

The protein kinase may comprise, CDK2 also known as p34CDK2, p33CDK2,p33CDK2.

The protein kinase may comprise PDGF also known as PDGFR1, PDGFR,PDGF-R-beta, JTK12, CD140B, PDGFRB.

The protein kinase may comprise kinase, FGFR-1 also known as N-SAM,LOC51033, FLT2, FLJ14326, CEK, C-FGR, BFGFR, H5, H4, H3, H2, FLG.

The protein kinase may comprise P38 MAP Kinase also known as p38alphap38ALPHA, SAPK2a, SAPK2A, PRKM15, PRKM14, Mxi2, MXI2, Exip, EXIP, CSPB1,CSBP2, CSBP1, p38, RK, P38, MAPK14.

In another form, the invention comprises a compound of formula I whichis a derivative of a furanose form of a monosaccharide of generalformula I,

-   -   Wherein;    -   n is 1,    -   X is selected from: OR1,

-   -   R1 and R3 are independently selected from the group consisting        of: C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7        heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14        arylalkyl and C3 to C14 heteroarylalkyl,    -   R4 is selected from the group consisting of: H, C1 to C7 alkyl,        C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to        C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to        C14 heteroarylalkyl,    -   R5 is selected from the group consisting of: H, C1 to C7 alkyl,        C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to        C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl or C3 to C14        heteroarylalkyl, C1 to C7 acyl, C6 to C14 arylacyl, and C3 to        C14 heteroarylacyl,    -   R2 is selected from —(C═O)—R3, —(C═O)—OR4, —(C═O)—NH—R4,    -   Y is selected from the group consisting of:

-   -   R6 is selected from the group consisting of H, C1 to C7 alkyl,        C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to        C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to        C14 heteroarylalkyl,    -   with the proviso that R6, R7 and R8 are not all H,    -   R9 is selected from H, or —(CO)—R6,    -   R7, R8, R11, R12, R14, are independently selected from the group        consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7        alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6        to C14 arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl,        C6 to C14 arylalkyl or C6 to C14 heteroarylalkyl,    -   R13 is selected from the group consisting of: unsubstituted        phenyl, unsubstituted benzyl, substituted phenyl, substituted        benzyl, H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl,        C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14        arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to        C14 arylalkyl or C6 to C14 heteroarylalkyl, —S—R6 or —O—R6,    -   R15 is absent or is at least one substituent on the aromatic        ring which is independently selected from the group consisting        of: OH, NO, NO₂, NH₂, N₃, halogen, CF₃, CHF₂, CH₂F, nitrite,        alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid,        carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl,        heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl,        aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted        imine, sulfate, sulfonamide, phosphate, phosphoramide,        hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, alkyl,        aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or        thioheteroaryl.

R7 and R8 may combine to form a cyclic structure.

R6 and one of R7 or R8 may combine to form a cyclic structure.

R11 and R12 may combine to form a cyclic structure.

R1, R2, R3, R4 and R5 are optionally substituted, cyclic or acyclic,branched and/or linear.

R2 and R3 may combine to form a ring structure.

R4 and R5 may combine to form a ring structure.

At least one of R1 to R5 may be substituted with a substituent selectedfrom the group, OH, NO, NO₂, NH₂, N₃, halogen, CF₃, CHF₂, CH₂F, nitrile,alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acidester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl,aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl,substituted or unsubstituted imine, sulfate, sulfonamide, phosphate,phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy,alkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl orthioheteroaryl, which may optionally be further substituted,

X may be

or —OR1.

Y may comprise A as described above.Y may comprise B as described above.Y may comprise C as described above.Y may comprise D as described above.Y may comprise E as described above.Y may comprise F as described above.Y may comprise G as described above.

The compounds of the invention may be mixed with a pharmaceuticalacceptable carrier, adjuvant, or vehicle which may comprise a-toxiccarrier, adjuvant, or vehicle that may be administered to a patient,together with a compound of this invention, and which does not destroythe pharmacological activity thereof.

The pharmaceutical derivative may comprise a salt, ester, salt of anester or other derivative of a compound of this invention which, uponadministration to a recipient, is capable of providing, either directlyor indirectly, a compound of this invention, although no limitation ismeant thereby.

Compounds of the invention may be administered orally such as by meansof a tabled, powder, liquid, emulsion, dispersion and the like; byinhalation; topically such as by means of a cream, ointment, salve etc;and as a suppository, although no limitation is meant thereby.

BEST MODE General Methods General Method 1—Amide Bond Formation:

To a solution of an acid in DMF (0.3 ml, 0.35 M, 1.0 equiv.) at roomtemperature was added a solution of HBTU in DMF (0.3 ml, 0.42 M, 1.2equiv.) followed by DIPEA (2.5 equiv.). After 10 min., a solution of thedesired amine in DMF (0.3 ml, 0.37 M, 1.05 equiv.) was added. Theresulting solution was stirred at room temperature for 2.5 h, thendiluted with DCM (8 ml) and washed with 10% citric acid (2×5 ml),saturated NaHCO₃ (2×5 ml), brine (5 ml) and water (5 ml). The solventwas removed in vacuo.

General Method 2—Ester Hydrolysis:

A solution of the ester (0.1 mmoles) in THF (0.5 ml) was treated with asolution of lithium hydroxide in water (0.5 ml, 0.45 M, 2.1 equiv.). Theresulting mixture was stirred at room temperature overnight, thenevaporated to dryness under reduced pressure to provide thecorresponding carboxyllic acid as the lithium salt. The residue isredissolved in either ethyl acetate or dichloromethane and washed with asmall quantity of 10% citric acid solution, followed by drying of theorganic layer and removal of the solvents in vacuo to yield the desiredcarboxylic acid. In cognate experiments sodium hydroxide or potassiumhydroxide has been substituted for lithium hydroxide to for thecorresponding sodium or potassium salts in comparable yields. Methanoland dioxane have been substituted for THF as the reaction solvent withcomparable results.

General Method 3a—Removal of Acid Labile Protecting Groups(Isopropylidene and BOC)— Solution Phase:

The compound was dissolved in acetonitrile and treated with 90/10trifluoroacetic acid-water (2 ml) and monitored by t.l.c for reactioncompleteness. Reaction times vary considerably from 15 minutes at RT to6 hours at RT. When complete, the mixture was concentrated under reducedpressure and co-evaporating from acetonitrile. The crude products wereresuspended in water-acetonitrile and lyophilised then purificatied byreverse phase C-18 HPLC using a solvent gradient of water/acetonitrileto afford the desired product as white solids. In cognate experiments,50/50 trifluoroacetic acid-water has been used with similar efficiency.

General Method 3b—Removal of Acid Labile Protecting Groups(Isopropylidene and BOC) and Cleavage from Resin—Solid Phase:

The resin bound compound (approx. 200 mg of resin) was washed with DCM(2×2 mL) then treated with TFA/DCM 1:1 (1 mL) for 15 mins. The resin wasfiltered and washed with acetonitrile (1 ml) (filtrates collected). Thisprocedure was repeated for a second cycle. The filtrates were evaporatedunder a stream of nitrogen. The residue was redissolved in water (1 ml)and agitated for 3 h. After this time, the solution was lyophilised toafford the crude products which were purified as described above.

General Method 4—Removal of an Fmoc Protecting Group:

The Fmoc protected compound on resin (12 g of resin, 0.7 mmol/g, 8.4mmol) was washed with DMF (2×120 ml), then treated with 20% piperidinein DMF (120 ml) and shaken at r.t. for 30 min. The resin was drained andwashed with DMF (2×120 ml). The reaction was repeated and the resin wasdrained, washed with DMF (2×120 ml), DCM (2×120 ml), MeOH (2×120 ml) andether (2×120 ml), and dried in vacuo for 2 h.

General Method 5—Coupling of Fluoro-Nitro-Benzoic Acid:

Resin bound substrate was washed under N₂ with dry DCM (1×80 ml, 1×60ml). To a solution of 4-fluoro-3-nitrobenzoic acid (9.3 g, FW 185.09,50.2 mmol, 6 equiv.) in dry DCM (60 ml) and dry DMF (9 ml) at r.t. andunder N₂ was added 1,3-diisopropylcarbodiimide (DIC, 3.9 ml, d 0.806, FW126.20, 24.9 mmol, 3 equiv.). The solution was stirred for 10 min., thenadded to the resin followed by 4-(dimethylamino)pyridine (DMAP, 102 mg,FW 122.17, 0.83 mmol, 0.1 equiv.). The resin was then shaken at r.t. for3 h, drained, washed with DMF (4×120 ml), DCM (3×120 ml) and ether(2×120 ml), and dried in vacuo overnight. The coupling procedure may berepeated in the event of a positive ninhydrin test.

General Method 6—Nucleophillic Aromatic Displacement:

Resin bound 3-nitro-4-fluoro-benzoate XI (200 mg, 0.14 mmol) was washedunder N₂ with dry DMF (2 ml) or dry DMSO (2 ml), then treated with asolution of the nucleophile (0.42 mmol, 3 equiv.) and diisopropylamine(DIPEA, 0.146 ml, d 0.742, FW, 129.25, 0.84 mmol, 6 equiv.) in dry DMF(2 ml) or dry DMSO (2 ml) and shaken at r.t. o/n. The resin was drainedand washed with DMF (3×2 ml) and DCM (3×2 ml). In the case of DMSO assolvent, the reaction was warmed to 60° C. The nucleophile may be anysuitable primary or secondary aliphatic or aromatic amine, or a thiol.In an alternative experiment, the nucleophile was bound to the solidsupport and treated with an excess of ortho-fluoro-nitrobenzylderivatives under similar conditions.

General Method 7—Reduction of an Aromatic Nitro Group:

The resin bound substrate (0.14 mmol) was washed with DMF (2×2 ml) andthen suspended in DMF (0.7 ml) to which was added a solution ofSnCl₂.2H₂O in DMF (0.7 ml, 2 M, 1.40 mmol, 10 equiv.). The resin wasshaken at r.t. o/n, then washed with DMF (5×2 ml), DCM (3×2 ml) and MeOH(5×2 ml).

General Method 8 Preparation and Reaction of an Acid Chloride:

Resin bound substrate (0.14 mmol) was washed with DCM (2×2 ml) and thenunder N₂ with dry DCM (2×2 ml). A suspension of the of sugar-acidbuilding blocks (0.42 mmol, 3 equiv.) in dry DCM (2 ml) was treated withtriphosgene (42 mg, FW 296.75, 0.14 mmol, 1 equiv.) followed bycollidine (0.159 ml, d 0.917, FW 121.18, 1.20 mmol, 8.6 equiv.). Aneffervescence was observed and a solution formed. After 1 min., thissolution was added to the resin bound substrate and the resin was shakenat r.t. for 3 h. The resin was drained and washed with DCM (5×2 ml) andMeOH (3×2 ml).

General Method 9 Cleavage of Adenosine N-Benzoyl Group:

The adenosine-containing products were treated with saturated ammonia inmethanol (4 ml) at r.t. o/n. The solvent was removed in vacuo and theproduct was again treated with sat NH₃ in MeOH at r.t. o/n. The solventwas removed in vacuo and compounds purified as described above. In analternative procedure, 1M hydrazine hydrate in DMF was substituted formethanolic ammonia. The latter procedure is particularly useful forbenzoate removal on solid support.

General Method 10—Benzimidazole Synthesis:

Resin bound substrate (approx. 200 mg, 0.14 mmol) was treated with asolution of an aldehyde (5.0 equivalents) in N-methylpyrrolidine (NMP)(4 ml) and heated to 45-50° C. overnight. The resins were subsequentlywashed with DMF (3×4 mL), DCM (3×4 mL), MeOH (3×4 mL), ether (3×4 mL)and dried in vacuo overnight.

General Method 11—Cesium Carboxylate Coupling:

The cesium salt of the Boc protected amino acid is made by dissolvingthe amino acid in methanol (5 ml/mmol) and water (0.5 ml/mmol) andadding an aqueous solution of 20% Cs₂CO₃ until pH 7 is reached. Thesolvent is removed in vacuo and the material is freeze-dried overnightto give a white powder. The resin is treated with the cesium salt (5 eq)in dry DMF (4 ml/g of resin) and stirred at 50° C. for 24 hours. Theresin is drained and washed with DMF, DMF/H₂O (1:1; ×3), MeOH/H₂O (1:1;×3) and MeOH (×3) and then dried in vacuo.

General Method 12—Reductive Amination:

6 eq of aldehyde is dissolved in TMOF/THF (1:1; 2 ml) and added to theresin (200 mg) and shaken at room temperature for 3-4 hours. The resinis drained and a solution of NaCNBH₃ (2 eq) in THF/MeOH/AcOH (9:1:0.1; 2ml) is added to the resin and shaken overnight at room temperature. Theresin is then drained and washed with THF/MeOH (1:3; ×3, DMF/MeOH (1:3;×3), DCM/MeOH (1:3; ×3) and DCM.

General Method 13—Urea Formation:

In a gloved box, the resin is swelled in 10% DIPEA/DCM, a solution oftriphosgene (2 eq in 1.2 ml of dry DCM) was added to the resin in twobatches and shaken for 1 hour. The resin is washed with dry DCM (1 ml×2)and a solution of the amine (1.1 eq) and DIPEA (2.2 eq) in 1.5 ml of dryDCM was added and shaken for 30 minutes. The resin is drained and washedwith DMF (×3), DCM (×3) and MeOH (×3) and dried.

General Method 14 Base Catalysed Ring Closure:

The resin was treated with a solution of MeOH/NEt₃ (9:1; 2 ml) andheated to 60° C. overnight. The resin is drained (collecting thefiltrate) and washed with MeOH, (1 ml), DCM (1 ml), MeOH (1 ml) and DCM(1 ml). The filtrates are combined and the solvent removed in vacuo. Theprocess is then repeated.

General Method 15—Thiourea Formation:

Resin bound substrate was washed under N₂ with dry THF (3×30 mL) thenthiocarbonyl diimidazole (2.49 g, 14 mmol) in dry THF (70 mL, conc=0.2M)was added and the resin was shaken at rt for 12 h. The resin wasfiltered, washed with THF (3×30 mL), DMF (2×30 mL), DCM (2×30 ml),DCM/MeOH (30 mL), MeOH (30 mL) and dried in vacuo.

General Method 16—S Alkylation of an Isothiourea:

The reactions were performed in Bodhan Miniblocks. The resin boundthiourea compound resin (200 mg) was washed under N₂ with dry DMF (2×2mL). Alkyl halide R¹X (0.7 mmol) in dry DMF (1 mL) was added followed byDIPEA (1.4 mmol) in dry DMF (1 mL). The resin was shaken at rt for 12 h,then washed with DMF (3×2 mL), DCM (3×2 mL), DCM/MeOH 1:1 (2×2 mL), MeOH(2×2 mL).

General Method 17—Bromoacetylation:

To bromoacetic acid (7.76 g) in dry DCM (40 mL) was added slowly DIC(4.4 mL) at 0° C. The solution was stirred at 0° C. for 30 mins. Thesolution was syringed out leaving the precipitated urea.

Resin bound substrate was washed under N₂ with dry DMF then swollen indry DMF (1 mL). The bromoacetic anhydride solution in dry DCM (1 ml) wasadded and the resin was shaken at rt for 1 hrs. The resin was filtered,washed with dry DMF (3×3 mL) under N₂ (glove box) and dry DCM (2×3 mL).Excess DCM was drained applying positive pressure of N₂. The resin wascarried through the next step immediately.

General Method 18-N-Alkylation:

Bromoacetylated resin produced by general method 17 is added to a sugaramine building block (5 eq) in DMF (1 mL). The resin was shaken at rtfor 16 h then filtered, washed with DMF, DCM, DCM/MeOH and dried invacuo.

General Method 19-Dichloro-Nitropyrimidine Addition:

The resin was swelled in NMP and a solution of4,6-Dichloro-5-nitropyrimidine (5 eq) and DIPEA (10 eq) in NMP (1 ml/100mg resin) was added and shaken at room temperature overnight (solutionturned deep orange-red). The resin was drained under nitrogen and washedwith dry DMF and dry DCM until filtrate is colourless and dried invacuo.

General Method 20—Nitro Reduction:

The resin was swelled in DCM (1.5 ml/100 mg) and a solution of K₂CO₃ (10eq) and Na₂S₂O₄ (8 eq) in H₂O (0.75 ml/100 mg) was added. Viologen (0.4eq) was then added turning the solution deep blue. The resin was thenshaken vigourously for 72 hours. The resin was then drained and washedwith an aqueous solution of 1% AcOH, THF, DMF and DCM and dried invacuo.

General Method 21—Aldehyde Cyclisation:

A solution of the aldehyde (5 eq) in NMP with 1% AcOH (800 μl/100 mgresin) was added to the dry resin in a test tube. The tube was sealedbut allowed to vent with a needle in the top. The resin was heated at100° C. overnight. The resin was filtered and washed with DMF, DCM andMeOH and dried in vacuo.

General Method 22—Acid Chloride Acylation:

Resin bound substrate was washed under N₂ with dry DCM then swollen inDIPEA (20 eq)/DCM (1 mL). A solution of acid chloride (10 eq) in DCM (1ml) was added and the resin was shaken at rt for 24 h. The resin waswashed with DMF, DMF/MeOH, DCM, DCM/MeOH, MeOH and dried in vacuo.

General Method 23—Reaction with the Isocyanates and the Resin Cleavage:

The resin was taken up in DCE and cooled to 0° C. followed by isocyanate(4 eq) addition. After 30 minutes, 10% TFA/DCM was added followed byshaking for 1 hour at room temperature. The resin was filtered andwashed with DCM. The filtrate was concentrated under reduced pressure toafford the crude residue.

General Method 24—Biological Assays:

Compounds were tested in vitro as follows.

Recombinant protein kinases, which were expressed as fusion proteins inSF9 insect cells or E. coli, were used for all in vitro assays. Thepurity and identity of each kinase was checked by SDS-PAGE/silverstaining and by western blot analysis with specific antibodies.

All kinase assays except for p38a (see below) were performed in 96-wellmicro-titre plates. The assay components included assay buffer, ATP,test compound, enzyme and substrate.

The assay for all enzymes (except for the PKC see below, contained 60 mMHEPES-NaOH, pH 7.5, 3 mM MgCl₂, 3 mM MnCl₂, 3 μM Na-orthovanadate, 1 mMDU, 0.1 μM [γ-³³P]-ATP (approx. 5×10⁵ cpm per well).

The assay for the PKCs contained 60 mM HEPES-NaOH, pH 7.5, 1 mM EDTA,1.25 mM EGTA, 5 mM MgCl₂, 1.32 mM CaCl₂, 5 μg/ml Phosphatidylserine, 1μg/ml 1.2 Dioleyl-glycerol, 1.2 mM DTT, 50 μg/ml PEG₂₀₀₀₀, 0.1 μM[γ-³³P]-ATP (approx. 5×10⁵ cpm per well).

The table below details the amounts of enzyme and substrate that wereused per well:

Screen- pool Enzyme Substrate # Kinase # (ng/50 μl) Substrate (ng/50 μl)1 KIT 1 50 Poly(Glu, Tyr)_(4:1) 125 2 EGF-R 4 50 Poly(Glu, Tyr)_(4:1)125 3 TIE2 3 100 Poly(Glu, Tyr)_(4:1) 125 4 PDGF- 3 100 Poly(Glu,Tyr)_(4:1) 500 Ralpha 5 FGF-R1 1 75 Poly(Glu, Tyr)_(4:1) 500 6 CDK2/CycA2 10 Histone H1 250 7 MET 7 100 Poly(Glu, Tyr)_(4:1) 125 8 VEGF-R2 2 50Poly(Glu, Tyr)_(4:1) 125 9 ABL 1 10 Poly(Ala, Glu, 250 Lys,Tyr)_(6:2:5:1) 10 PKC-beta1 1 13 Histone H1 500

The reaction cocktails were incubated at 30° C. for 80 minutes. Thereaction was stopped with 50 μl of 2% (v/v) H₃PO₄, plates were aspiratedand washed twice with 200 μl of H₂O or 0.9% (w/v) NaCl. Incorporation of³³P_(i) was determined with a microplate scintillation counter.

The mitogen-activated protein kinase p38α assays were done in aproprietary microassay NanoCarrier™ 2080 format. In these assaysphosphorylation was detected by a phospho-substrate specific monoclonalantibody in an indirect competition assay. The degree of binding of theantibody to the phospho-substrate was measured by fluorescencepolarization using 2D-FIDA anisotrophy. In these experiments the finalconcentration of the enzyme was 1.6 nM and the substrate was 2 μM.

All data is presented as residual activity, which is the activity of theenzyme in the presence of the stipulated concentration of inhibitor orcompound. 100% activity is the maximum activity of the enzyme in theabsence of any inhibitor or compound.

In all experiments the Z′ value was calculated according to Zhang et alto (J-H Zhang, T. D. Y Chung, K. R. Oldenburg (1999) Journal ofBiomolecular Screening 4:67-73) using the standard deviations and meanvalues of the positive and negative controls.

Z′=1−(3*Stdev _(neg)+3*Stdev _(pos))/(Mean_(pos)−Mean_(neg))

Only data where the Z′ value was >0.5 was used.

Example 1

(1-a) General Method 1, (1-b) General Method 2, (1-c) General Method 3.

Analysis of Some Typical Example Compounds

Isomer A: proton (400 MHz: DMSO) 2.38 (dt, J 5.0, 6H, CH₂CH₂), 2.65 (d,J=15.0 Hz, 1H, CH₃), 3.85-3.95 (m, 2H, H2 or H3 or H4), 4.05 (dd, J 3.0,8.0 Hz, 1H, H5a), 4.10 (dd, J 3.0, 8.0 Hz, 1H, H5b), 4.30 (m, 1H, CH),4.65 (dd, J 5.0, 5.0 Hz, 1H, H2 or H3 or H4), 5.87 (d, J 4.0 Hz, 1H,H1), 8.30 (s, 1H, ArH), 8.45 (s, 1H, ArH).

Isomer B: proton (400 MHz: DMSO) 2.42 (dt, J 5.0, 6H, CH₂CH₂), 2.75 (d,J 15.0 Hz, 1H, CH₃), 3.85-3.95 (m, 2H, H2 or H3 or H4), 4.05 (dd, J 3.0,8.0 Hz, 1H, H5a), 4.10 (dd, J 3.0, 8.0 Hz, 1H, H5b), 4.30 (m, 1H, CH),4.65 (dd, J 5.0, 5.0 Hz, 1H, H2 or H3 or H4), 5.92 (d, J=4.0 Hz, 1H,H1), 8.35 (s, 1H, ArH), 8.50 (s, 1H, ArH).

Example 2

(2-a) General Method 1, (2-b) General Method 2, (2-c) General Method 3.

Analysis of Some Typical Example Compounds

proton (400 MHz: D₂O) 2.36-2.55 (m, 5H, alkyl H), 2.57-2.76 (m, 1H,alkyl H), 3.31-3.48 (m, 2H, H5), 3.98-4.07 (m, 1H, H4), 4.45-4.56 (m,2H, H3, NCHCO), 4.69-4.75 (m, 2H, H2), 5.57 (d, J 2.4 Hz, 1H, H1),7.32-7.40 (m, 2H, PhH), 7.41-7.53 (m, 3H, PhH).

proton (400 MHz: D₂O) 2.26-2.40 (m, 4H, alkyl H), 2.73 (dd, J 14.0, 8.0Hz, 1H, CHaPh), 2.88 (dd, J 14.0, 6.2 Hz, 1H, CHbPh), 3.30 (dd, J 14.6,4.6 Hz, 1H, H5a), 3.42 (dd, J 14.6, 3.8 Hz, 1H, H5b), 3.96-4.02 (m, 1H,H4), 4.26 (t, J=5.8 Hz, 1H, H3), 4.36 (t, J 7.4 Hz, 1H, NCHCO), 5.52 (d,J 2.8 Hz, 1H, H1), 7.02-7.20 (m, 5H, PhH), 7.35 (d, J 6.4 Hz, 2H, PhH),7.42-7.54 (m, 3H, PhH).

proton (400 MHz: D₂O) 1.76-1.87 (m, 1H, alkyl H), 1.96-2.08 (m, 1H,alkyl H), 2.30-2.41 (m, 6H, alkyl H), 3.43 (d, J 4.4 Hz, 2H, H5), 4.06(q, J 5.2 Hz, 1H, to H4), 4.26 (dd, J 9.0, 5.2 Hz, 1H, H3), 4.40 (t, J5.6 Hz, 1H, NCHCO), 4.69-4.74 (m, 1H, H2), 5.54 (d, J 3.2 Hz, 1H, H1),7.2.8-7.48 (m, 8H, PhH), 7.65 (s, 1H, PhH).

proton (400 MHz: D₂O) 0.77 (t, J 7.4 Hz, 3H, CH₂CH₃), 1.42-1.56 (m, 2H,CH₂CH₃), 2.37-2.53 (m, 5H, alkyl H), 2.58 (dd, J 15.4, 5.4 Hz, 1H, alkylH), 2.89 (t, J 7.6 Hz, 2H, ArCH₂), 3.30-3.46 (m, 2H, H5), 4.07-4.15 (m,1H, H4), 4.42-4.53 (m, 2H, H3, NCHCO), 4.70-4.75 (m, 2H, H2), 5.87 (d, J2.8 Hz, 1H, H1).

proton (400 MHz: D₂O) 0.78 (t, J 7.2 Hz, 3H, CH₂CH₃), 1.38-1.46 (m, 2H,CH₂CH₃), 2.34 (bs, 4H, alkyl H), 2.70 (t, J 10.2 Hz, 1H, ArCH_(a)),2.74-2.96 (m, 3H, ArCH_(D), CH₂Ph), 3.25-3.45 (m, 2H, H5), 4.02-4.12 (m,1H, H4), 4.18-4.25 (m, 2H, H3), 4.29-4.38 (m, 1H, NCHCO), 5.83 (bs, 1H,H1), 6.99-7.20 (m, 5H, PhH).

proton (400 MHz: O₂O) 0.73 (t, J 7.4 Hz, 3H, CH₂CH₃), 1.36-1.50 (m, 2H,CH₂CH₃), 1.73-1.85 (m, 1H, alkyl H), 1.88-2.03 (m, 1H, alkyl H),2.28-2.45 (m, 6H, alkyl H), 2.84 (q, J 7.5 Hz, 2H, ArCH₂), 3.42 (d, J4.4 Hz, 2H, H5), 4.10-4.20 (m, 2H, H3, H4), 4.38 (t, J 5.4 Hz, 1H,NCHCO), 5.84 (d, J 2.8 Hz, 1H, H1), 7.34-7.52 (m, 3H, ArH), 7.65 (s, 1H,ArH).

Some Typical Peptide Arms IIa-IIr Used in Step a of Examples 1 and 2

Example 3

(3-a) General Method 4, (3-b) General Method 5, (3-c) General Method 6(using reagents ArNH₂ and DMSO), (3-d) General Method 6 (using reagentsArCH₂NH₂ and DMF as solvent), (3-e) General Method 7, (3-f) GeneralMethod 7, (3-g) General Method 8, (3-h) General Method 3b, effects ringclosure, deprotection and cleavage from resin, (3-l) General Method 9,only required for adenine containing compounds.

Blocks IX, X and XI

Analysis of a Typical Example Compound

proton (400 MHz: d₆ DMSO) 4.92 (q, J 4.4 Hz, 1H, H2 or H3), 4.98 (q, J5.1 Hz, 1H, H2 or H3), 5.33 (d, J 4.0 Hz, 1H, H4), 5.54 (d, J 16.8 Hz,1H, CH_(a)Ph), 5.62 (d, J 17.2 Hz, 1H, CH_(b)Ph), 5.77 (d, J 5.3 Hz, 1H,OH), 5.80 (d, J 5.4 Hz, 1H, OH), 6.10 (d, J 5.3 Hz, 1H, H1), 6.96 (d, J7.9 Hz, 1H, PhH), 7.09 (t, J 7.8 Hz, 1H, PhH), 7.24 (bs, 2H, NH₂), 7.27(bs, 1H, PhH), 7.29 (s, 1H, CONH_(a)), 7.36 (d, J 8.9 Hz, 1H, PhH), 7.47(d, J 8.3 Hz, 1H, ArH), 7.78 (dd, J 8.5, 1.6 Hz, 1H, ArH), 7.98 (bs, 2H,ArH, CONH_(b)), 8.31 (d, J 1.2 Hz, 1H, ArH), 8.37 (s, 1H, ArH).

Example 4

(4-c) General Method 6 using a sugar amine, (4-d) General Method 7,(4-e) General Method 10, (4-f) General Method 3b, (4-g) General Method9, only required for adenine containing compounds.

Exemplary Aldehydes Used in Step 4-e

Benzaldehyde, 3-Bromobenzaldehyde, m-Tolualdehyde,2-Methoxybenzaldehyde, p-Tolualdehyde, 4-Dimethylaminobenzaldehyde,4-Cyanobenzaldehyde, 1,2,3,6-tetrahydrobenzaldehyde,Indole-3-carboxaldehyde, 2-naphthaldehyde, 3-methylthiophene-2-carboxaldehyde, cyclohexane carboxaldehyde,pyrrole-2-carboxaldehyde, phenyl acetaldehyde,4-(2-pyridyl)benzaldehyde, α,α,α-trifluoro-o-tolualdehyde,2,5-dimethylbenzaldehyde, 3,5-difluorobenzaldehyde,2-fluorobenzaldehyde, 4-fluoro-3-(trifluoromethyl)benzaldehyde.

Example 5

(5-a) General Method 1, (5-b) General Method 4, (5-c) General Method 6,(5-d) General Method 7, (5-e) General Method 3b

Analysis of Some Typical Example Compounds

proton (400 MHz: d₆ DMSO) 2.41 (s, 3H, CH₃), 3.83 (s, 3H, OCH₃),4.34-4.53 (m, 4H, H2, H3, H4, H5a), 4.75 (d, J 13.2 Hz, 1H, H5b), 5.80(s, 1H, H1), 6.97 (d, J 8.8 Hz, 2H, ArH), 7.39-7.47 (m, 21-1, ArH), 7.51(bs, 1H, NHa), 7.57-7.67 (m, 3H, ArH), 7.69-7.75 (m, 1H, ArH), 7.79 (bs,1H, NHb).

proton (400 MHz: d₆ DMSO) 0.77 (t, J 7.4 Hz, 3H, CH₂CH₃), 1.40 (q, J 7.1Hz, 2H, CH₂CH₃), 2.37 (s, 3H, ArCH₃), 2.84-2:98 (m, 2H, ArCH₂),4.38-4.52 (m, 4H, H2, H3, H4, H5a), 4.70 (bd, J 14.4 Hz, 1H, H5b), 5.80(s, 1H, H1), 6.85 (d, J 8.0 Hz, 2H, ArH), 7.27 (bs, 2H, NHa, ArH),7.48-7.60 (m, 4H, ArH), 7.78 (bs, 1H, NHb).

proton (400 MHz: d₆ DMSO) 3.77 (s, 3H, OCH₃), 4.35-4.46 (m, 3H, H2, H3,H4), 4.57 (bdd, J 14.8, 6.4 Hz, 1H, H5a), 4.84 (bd, J 14.8 Hz, 1H, H5b),5.05 (d, J 11.6 Hz, 1H, OCHa), 5.11 (d, J 11.6 Hz, 1H, OCHb), 5.34 (s,1H, H1), 6.96-7.04 (m, 4H, ArH), 7.20 (d, J 8.8 Hz, 2H, ArH), 7.30-7.46(m, 7H, ArH), 7.54 (bs, 1H, NHa), 7.60 (d, J 8.8 Hz, 2H, ArH), 7.63-7.68(m, 1H, ArH), 7.71-7.78 (m, 1H, ArH), 7.90 (bs, 1H, NHb).

Example 6

Conditions:

(a) general method 5 (b) general method 6; (c) general method 7, generalmethod 10; (d) general method 9 for adenosine containing compounds only,general method 3b.

Example 7

Example 8

(8-a) General Method 11, (8-b) General Method 3b, (8-c) General Method12, (8-d) General Method 13, (8-e) General Method 14, (8-f) GeneralMethod 3a, (8-g) General Method 9 for adenosine containing compounds.

Analysis of Some Typical Example Compounds

Isomer 1:

proton NMR (400 MHz, d₆-DMSO): δ: 8.46 (s, 1H, H-6); 8.26 (d, 1H, H-8);7.93 (s, 2H, NH₂); 7.37-7.31 (m, 6 h); 7.15-7.08 (m, 5H); 6.92 (d, 1H,J=6 Hz); 5.86 (d, 1H, J=5.6 Hz, H-1); 4.70-4.64 (m, 2H, containing H-2and H_(β1ald)); 4.39 (d, 1H, J=16 Hz, H_(β2ald)); 4.20 (t, 1H, J=4.8 Hz,H_(α)); 4.04-3.96 (m, 2H, containing H-3, H-5A); 3.59 (d, 1H, J=6.8 Hz,H-4); 2.97 (m, 2H, containing H_(β1), H_(β2)).

Isomer 2:

proton NMR (400 MHz, d₆-DMSO): δ: 8.42 (s, 1H, H-6); 8.22 (d, 1H, H-8);7.75 (s, 2H, NH₂); 7.38-7.30 (m, 6 h); 7.17-7.11 (m, 5H); 6.98-6.96 (m,1H, J=6 Hz); 5.82 (d, 1H, J=5.6 Hz, H-1); 4.72-4.64 (m, 2H, containingH-2 and H_(β1ald)); 4.40 (d, 1H, J=16.4 Hz, H_(β2ald)); 4.21 (t, 1H,J=4.4 Hz, H_(α)); 4.08 (t, 1H, J=4.4 Hz, H-3); 3.97 (q, 1H, J=6.4, 10.4Hz, H-5A); 3.65 (dd, 1H, J=6.4, 14.4 Hz, H-4); 3.54 (dd, 1H, J=7.6,14.4, H-5A); 2.98 (d, 2H, J=4.8 Hz containing H_(β1), H_(β2)).

Isomer 1:

proton NMR (400 MHz, d₆-DMSO): δ: 8.48 (s, 1H, H-6); 8.27 (s, 1H, H-8);7.45 (d, 1H, J=4.4 Hz); 7.40 (d, 1H, J=4.8 Hz); 7.24-7.09 (m, 4H);7.05-7.02 (m, 1H); 6.97-6.91 (m, 2H); 5.84 (d, 1H, J=6.4 Hz, H-1); 4.86(d, 1H, J=16 Hz, H_(β1ald)); 4.66-4.63 (m, 1H, H-2); 4.45 (d, 1H, J=16Hz, H_(β2ald)); 4.21 (t, 1H, J=4.4 Hz, H_(α)); 4.03 (t, 1H, J=3.6 Hz,H-3); 3.98-3.92 (m, 1H, H-5A); 3.19 (q, 1H, J=5.2, 9.2 Hz H_(β1));3.05-3.01 (m, 1H, H_(β2)).

Isomer 2:

proton NMR (400 MHz, d₆-DMSO): δ: 8.47 (s, 1H, H-6); 8.26 (s, 1H, H-8);7.44 (d, 1H, J=4 Hz); 7.41 (d, 1H, J=4.8 Hz); 7.24-7.09 (m, 4H);7.05-7.02 (m, 1H); 6.97-6.91 (m, 2H); 5.82 (d, 1H, J=6.4 Hz, H-1); 4.88(d, 1H, J=16 Hz, H_(β1ald)); 4.66-4.63 (m, 1H, H-2); 4.45 (d, 1H, J=16Hz, H_(β2ald)); 4.22 (t, 1H, J=4.4 Hz, H_(α)); 4.06 (t, 1H, J=4 Hz,H-3); 3.98-3.92 (m, 1H, H-5A); 3.22 (q, 1H, J=5.2, 9.2 Hz H_(β1));3.05-3.01 (m, 1H, H_(β2)).

proton NMR (400 MHz, d₆-DMSO): δ: 8.37 (s, 1H, H-6); 8.12 (s, 1H, H-8);7.63 (t, 4H, J=8.4 Hz); 7.46 (t, 2H, J=7.6 Hz); 7.36-7.27 (m, 5H); 5.87(d, 1H, J=5.6 Hz, H-1); 5.53 (d, 1H, J=6.4 Hz); 5.35 (d, 1H, J=4.8),4.78 (q, 1H, J=5.2, 10.4 Hz); 4.51 (s, 2H), 4.17-4.08 (m, 2H); 3.92 (s,2H); 3.82-3.77 (m, 1H); 3.70-3.64 (m, 1H).

proton NMR (400 MHz, d₆-DMSO): δ: 7.78 (s, 1H); 7.42 (s, 1H); 7.08 (d,1H, J=4 Hz); 6.88 (d, 1H, J=3.6 Hz); 5.77 (d, 1H, J=2.8 Hz); 4.62-4.60(m, 1H); 4.54 (s, 2H); 4.39 (t, 1H, J=5.2 Hz); 4.16 (q, 1H, J=6, 11.6Hz); 3.85 (d, 2H, J=5.2 Hz); 3.62-3.57 (m, 1H); 3.53-3.48 (m, 1H);3.02-2.90 (m, 3H); 1.54-1.48 (m, 2H); 0.86-0.83 (m, 3H).

Isomer 1:

proton NMR (400 MHz, d₆-DMSO): δ: 8.40 (s, 1H); 8.18 (s, 1H); 7.62 (s,2H); 7.56 (d, 2H, J=7.6 Hz); 7.44 (t, 2H, J=3.6 Hz); 7.37 (t, 3H, J=8.4Hz); 7.27-7.25 (m, 3H); 7.20-7.18 (m, 2H); 7.08 (d, 2H, J=8 Hz); 5.87(d, 1H, J=5.6 Hz); 4.76 (d, 1H, J=15.6 Hz); 4.67 (t, 1H, J=5.6 Hz); 4.30(d, 1H, J=15.6 Hz); 4.23 (t, 1H, J=4.4 Hz); 4.04-4.00 (m, 2H); 3.70-3.59(m, 2H); 3.18-3.04 (m, 2H).

Isomer 2:

proton NMR (400 MHz, d₆-DMSO): δ: 8.39 (s, 1H); 8.20 (s, 1H); 7.81 (s,2H); 7.61 (d, 2H, J=7.2 Hz); 7.52 (d, 2H, J=8 Hz); 7.45 (t, 3H, J=7.2Hz); 7.35-7.26 (m, 5H); 7.21 (dd, 4H, J=6.8, 15.6); 5.83 (d, 1H, J=6Hz); 4.78 (d, 1H, J=15.6 Hz); 4.69 (t, 1H, J=5.2 Hz); 4.30 (d, 1H,J=15.6 Hz); 4.25 (t, 1H, J=4.4 Hz); 4.11 (t, 1H, J=4.4 Hz); 4.02-3.98(m, 2H); 3.21-3.06 (m, 2H); 3.18-3.04 (m, 2H).

Isomer 1

proton NMR (400 MHz, d₆-DMSO): δ: 8.46 (s, 1H); 8.25 (s, 1H); 7.63 (d,4H, J=7.2 Hz); 7.52 (t, 2H, J=7.6 Hz); 7.44-7.36 (m, 5H); 7.28 (d, 2H,J=8.4 Hz); 7.16 (d, 2H, J=8.4 Hz); 5.95 (d, 1H, J=5.6 Hz); 4.79-4.73 (m,2H); 4.40-4.33 (m, 2H); 4.13-4.07 (m, 2H); 3.78-3.70 (m, 2H); 3.26-3.11(m, 2H).

Isomer 2

proton NMR (400 MHz, d₆-DMSO): δ: 8.26 (s, 1H); 8.07 (s, 1H); 7.55 (d,2H, J=7.4 Hz); 7.45 (d, 2H, J=8.4 Hz); 7.39 (t, 5H, J=7.6 Hz); 7.30 (d,2H, J=8 Hz); 7.17 (d, 2H, J=8.4 Hz); 7.11 (d, 2H, J=8.4 Hz); 5.77 (d,1H, J=5.6 Hz); 5.50 (s, 1H); 5.26 (s, 1H); 4.67-4.63 (m, 2H); 4.25-4.22(m, 2H); 4.06 (t, 1H, J=8 Hz); 3.95 (q, 1H, J=6.8, 10.4 Hz); 3.67-3.48(m, 2H); 3.18-2.99 (m, 2H).

Example 9

Conditions:

(a) general method 1; (b) (I) MsCl, DCM, (ii) Tryptamine derivative, DMF(c) R₃CHO, 25% TFA/DCM, rt; (d) general method 3b.

Example 10

Conditions:

(a) (i) general method 4, (ii) o-nitrobenzenesulfonyl chloride, DCM,DIPEA, 3 hours, RT; (b) PPh₃, aminoalcohol, DEAD, 24 hr; (c) (i) generalmethod 4, (ii) general method 12; (d) (i) Na⁺PhS⁻, DMF, 12 hours, RT(ii) general method 13 where the amine is intramolecular, (e) generalmethod 3b.

Example 11

Conditions:

(a) DMF, DIPEA; (b) general method 1; (c) general method 3b; (d) refluxin toluene.

Example 12

Conditions:

(a) aldehyde, TMOF/THF; (b) general method 4; (c) general method 12;(d)) (i) Na⁺PhS⁻, DMF, (ii) general method 13 where the second amine isintramolecular; (e) general method 3b

Example 13

Conditions:

(a) R2-isothiocyanate, DCM; (b) Bromoketone, DMF; (c) general method 3b

Example 14

Conditions:

(a) R₂CHO, TMOF, THF; (b) R₃—CO—Cl, NEt₃; (c) general method 3b.

Example 15

Conditions:

(a) Epoxide, DIEA, DMF; (b) CDI, DCM; (c) general method 3b.

Example 16

Conditions:

(a) R₃—CO—CO—R₄, NH₄OAc, R₂—CHO; (b) general method 3b

Example 17

Conditions:

(a) R₂CHO, TMOF, THF; (b) mercapto acetic acid; (c) general method 3b.

Example 18

(18-a) General Method 15, (18-b) General Method 16, (18-c) GeneralMethod 9, hydrazine/DMF conditions for adenosine containing compoundsonly, (18-d) General Method 3b

Exemplary Yield and Crude Product Purity

Ra=adenosine

Purity of crude cpds Compound (%, by ELSD) yield (%) 86 96 33 87 92 3388 84 31 89 98 31 90 97 27 91 96 46 92 92 35 93 87 28 94 86 34 95 98 4096 85 33 97 95 35 98 94 45 99 97 39 100 98 39 101 96 40 102 98 47 103 6323 104 90 38 105 96 31 106 95 49 107 98 46 108 41 18 109 89 38 110 89 41111 81 18 112 20 12 113 15 8 114 35 12 115 95 22 116 84 42 117 97 39 11888 34 119 77 25 120 92 44

Analysis of Some Typical Example Compounds

proton (400 MHz, d⁶-DMSO): 8.29 (s, 1H, H-8), 8.11 (s, 1H, H-2), 8.00(d, 1H, J=1.5 Hz, Ar—H), 7.87 (broad s, 1H, NH), 7.61 (dd, 1H, J=1.5,8.6 Hz, Ar—H), 7.41 (d, 1H, J=8.6 Hz, ArH), 7.30 (broad s, 2H, NH), 7.21(broad s, 1H, NH), 5.86 (d, 1H, J=5.1 Hz, H′-1), 5.61 (d, 1H, J=6.0 Hz,OH), 5.45 (d, 1H, J=5.4 Hz, OH), 4.72 (qua, 1H, J=5.2 Hz, H′-2 or H′-3),4.54 (dd, J=15.2, 4.7 Hz, H′-5), 4.47 (dd, 1H, J=15.2, 7.4 Hz, H′-5),4.31 (qua, 1H, J=4.7 Hz, H′-3 or H′-2), 4.29 (dt, 1H, J=4.7, 7.4 Hz).

carbon (100 MHz, d⁶-DMSO): 168.7, 156.6, 154.8, 153.2, 149.8, 142.9,140.4, 139.3, 128.4, 121.9, 119.8, 117.6, 109.8, 88.5, 82.7, 73.5, 71.8,46.9.

proton (400 MHz, d⁶-DMSO): 8.38 (s, 1H, H-8), 8.15 (s, 1H, H-2), 7.95(broad s, 1H, NH), 7.64 (d, 1H, J=1.5 Hz, Ar—H), 7.54 (dd, 1H, J=1.5,8.3 Hz, Ar—H), 7.31 (d, 1H, J=8.5 Hz, Ar—H), 7.30 (broad s, 1H, NH),7.25 (broad s, 1H, NH), 5.85 (d, 1H, J=6.3 Hz, H′-1), 5.54 (d, 1H, J=6.2Hz, OH), 5.38 (d, 1H, J=5.1 Hz, OH), 4.82 (qua, 1H, J=5.8 Hz, H′-3 orH′-2), 4.70 (dd, 1H, J=4.6, 13.8 Hz, H′-5), 4.49-4.38 (m, 2H, H′-5H′-4),4.35 (m, 1H, H′), 2.10 (s, 3H, CH₃).

carbon (100 MHz, d⁶-DMSO): 170.2, 167.9, 156.6, 153.2, 150.0, 140.4,135.9, 131.1, 129.6, 122.3, 119.8, 110.0, 109.7, 87.8, 82.4, 73.2, 71.9,46.9, 31.5.

proton (400 MHz, d⁶-DMSO): 8.30 (s, 1H, H-8), 8.11 (s, 1H, H-1), 8.08(d, 1H, J=1.5 Hz, Ar—H), 7.59 (broad s, 1H, NH), 7.63 (dd, 1H, J=1.5,8.3 Hz, Ar—H), 7.43 (d, 1H, J=8.3 Hz, Ar—H), 7.31 (broad s, 2H, NH₂),7.22 (broad s, 1H, NH), 5.87 (d, 1H, J=5.0 Hz, H′-1), 5.63 (d, 1H, J=5.8Hz, OH), 5.46 (d, 1H, J=5.4 Hz, OH), 4.75 (qua, 1H, J=5.0 Hz, H′-2 orH′-3), 4.54 (dd, 1H, J=4.7, 15.3 Hz, H′-5), 4.48 (dd, 1H, J=7.6, 15.3Hz, H′-5), 4.34 (qua, 1H, J=4.7 Hz, H′-2 or H′-3), 4.25 (dt, 1H, J=4.7,7.4 Hz, H′-4), 3.24 (qua, 2H, J=7.3 Hz, CH₂), 1.32 (t, 3H, J=7.3 Hz,CH₃).

carbon (100 MHz, d⁶-DMSO): 168.7, 156.6, 153.8, 153.2, 149.8, 143.0,140.4, 139.1, 128.4, 121.9, 119.8, 117.6, 109.9, 88.5, 82.7, 73.4, 71.8,46.9, 27.2, 15.6.

Yield and Purity of Crude Products Ra=

Purity of Crude cpds Compound# R¹ (%, by ELSD) yield (%) 121 Ph 96.9 38122 Ph 94.8 5 123 Ph 96.7 31 124 Ph 97.8 34 125 Ph 50.6 38 126 Ph 97.321 127 Ph 98.3 41 128 Ph 97.7 26 129 Ph 97.7 14 130 Ph 96.7 28 131 Ph91.1 23 132 Ph 97.9 39 133 Ph 96.9 36 134 Ph 89.0 31 135 Ph 97.5 33 136Ph 96.4 22 137 Ph 97.0 30 138 Ph 96.7 28 139 Ph 84.6 23 140 Ph 83.3 24141 Ph 97.1 28 142 Ph 97.0 27 143 Ph 95.3 35 144 Ph 72.8 25 145 Ph 88.630 146 Ph 85.7 8 147 Ph 66.3 23 148 Ph 68.1 25 149 Ph 26.1 15 150 Ph97.7 7 151 Ph 99.1 5 152 Ph 97.8 6 153 Ph 48.4 17 154 Ph 95.6 26 155 Ph96.0 31 156 Ph 74.50 2 157 Ph 7.9 3 158 Ph 53.6 17 159 Pr 96.4 12 160 Pr98.2 37 161 Pr 96.8 20 162 Pr 96.9 36 163 Pr 97.4 19 164 Pr 96.4 36 165Pr 96.7 27 166 Pr 97.2 24 167 Pr 96.8 17 168 Pr 95.0 33 169 Pr 82.1 15170 Pr 95.8 34 171 Pr 97.0 37 172 Pr 97.4 23 173 Pr 96.8 33 174 Pr 96.937 175 Pr 96.9 41 176 Pr 96.9 28 177 Pr 89.9 7 178 Pr 98.2 35 179 Pr97.3 37 180 Pr 96.4 36 181 Pr 93.7 28 182 Pr 80.7 26 183 Pr 96.6 36 184Pr 97.7 36 185 Pr 60.2 21 186 Pr 86.9 33 187 Pr 39.7 15 188 Pr 97.2 2189 Pr 99.5 60 190 Pr 98.4 4 191 Pr 60.0 5 192 Pr 96.0 34 193 Pr 96.7 36194 Pr 95.4 12 195 Pr 17.0 2 196 Pr 80.5 11

Analysis of a Typical Example Compounds

proton (400 MHz, d⁶-DMSO): 8.13 (d, 1H, J=1.3 Hz, Ar—H), 8.09 (d, 1H,J=8.7 Hz, Ar—H), 7.93 (broad s, 1H, NH), 7.86 (broad s, 1H, NH), 7.70(dd, 1H, J=1.3, 8.4 Hz, Ar—H), 7.64 (d, 1H, J=8.7 Hz, Ar—H), 7.50-7.30(m, 5H, Ar—H), 7.28 (d, 1H, J=8.5 Hz, Ar—H), 7.25 (broad s, 1H, NH),5.75 (d, 1H, J=5.48 Hz, OH), 5.53 (d, 1H, J=6.4 Hz, OH), 5.37 (d, 1H,J=1.7 Hz, H′-1), 4.75-4.60 (m, 3H, CH+CH₂), 4.54-4.40 (m, 2H, CH),4.30-4.23 (m, 2H, CH).

Carbon (100 MHz, d⁶-DMSO): 167.6, 161.1, 152.2, 146.2 145.3, 141.8,138.9, 138.2, 138.1, 129.9, 129.7, 129.4, 127.8, 127.7, 125.0, 123.2,121.3, 116.9, 108.8, 89.7, 82.3, 74., 71.8, 46.3, 34.7.

Example 19

(19-a) General Method 17, (19-b) General Method 18, (19-c) GeneralMethod 9 for adenosine containing compounds only, (19-d) General Method3b.

Retention time, observed mass, yield Compound 2 components 19-III and19-IV 312 Rt = 4.24 min (M + H)⁺ = 516 (26%), Rt = 4.75 min (M + H)⁺ =544 (72%) 313 Rt = 4.80 min (M + H)⁺ = 550 (3%), Rt = 5.28 min (M + H)⁺= 578 (72%) 314 Rt = 4.52 min (M + H)⁺ = 546 (23%), Rt = 4.96 min (M +H)⁺ = 574 (74%) 315 Rt = 4.70 min (M + H)⁺ = 530 (11%), Rt = 5.17 min(M + H)⁺ = 558 (88%) 316 Rt = 4.69 min (M + H)⁺ = (2%), Rt = 5.23 min(M + H)⁺ = (19%) 317 Rt = 5.82 min (M + H)⁺ = 572 (22%), Rt = 6.26 min(M + H)⁺ = 544 (78%) 318 Rt = 4.81 min (M + H)⁺ = 596 (73%), Rt = 5.40min (M + H)⁺ = 624 (27%) 319 Rt = 4.68 min (M + H)⁺ = 530 (2%), Rt =5.15 min (M + H)⁺ = 558 (98%) 320 Rt = 5.92 min (M + H)⁺ = 608 (25%), Rt= 6.37 min (M + H)⁺ = 636 (75%) 321 Rt = 5.97 min (M + H)⁺ = 622 (52%),Rt = 6.48 min (M + H)⁺ = 650 (48%) 322 Rt = 5.74 min (M + H)⁺ = 592(43%), Rt = 6.27 min (M + H)⁺ = 620 (57%) 323 Rt = 5.15 min (M + H)⁺ =569 (14%), Rt = 5.98 min (M + H)⁺ = 597(86%) 324 Rt = 5.63 min (M + H)⁺= 603 (46%), Rt = 6.62 min (M + H)⁺ = 631(52%) 325 Rt = 5.34 min (M +H)⁺ = 599 (23%), Rt = 6.20 min (M + H)⁺ = 627 (77%) 326 Rt = 5.51 min(M + H)⁺ = 583 (38%), Rt = 6.38 min (M + H)⁺ = 611 (62%) 327 Rt = 5.58min (M + H)⁺ = 603 (90%), Rt = 6.46 min (M + H)⁺ = 631 (8%) 328 Rt =6.54 min (M + H)⁺ = 625 (55%), Rt = 7.41 min (M + H)⁺ = 653 (45%) 329 Rt= 5.77 min (M + H)⁺ = 647 (31%), Rt = 6.66 min (M + H)⁺ = 677 (55%) 330Rt = 5.59 min (M + H)⁺ = 612 (28%), Rt = 6.20 min (M + H)⁺ = 640 (61%)331 Rt = 5.51 min (M + H)⁺ = 583 (22%), Rt = 6.31 min (M + H)⁺ = 611(78%) 332 Rt = 6.57 min (M + H)⁺ = 661 (42%), Rt = 7.50 min (M + H)⁺ =689 (58%) 333 Rt = 6.75 min (M + H)⁺ = 675 (38%), Rt = 7.62 min (M + H)⁺= 703 (60%) 334 Rt = 6.56 min (M + H)⁺ = 645 (55%), Rt = 7.38 min (M +H)⁺ = 673 (44%) 335 Rt = 5.03 min (M + H)⁺ = 535 (17%), Rt = 5.77 min(M + H)⁺ = 563 (82%) 335 Rt = 5.58 min (M + H)⁺ = 569 (11%), Rt = 6.35min (M + H)⁺ = 597 (87%) 336 Rt = 5.26 min (M + H)⁺ = 565 (15%), Rt =6.0 min (M + H)⁺ = 593 (84%) 337 Rt = 5.33 min (M + H)⁺ = 5.49 (12%), Rt= 6.04 min (M + H)⁺ = 577 (88%) 338 Rt = 5.41 min (M + H)⁺ = 569 (79%),Rt = 6.27 min (M + H)⁺ = 597 (5%) 339 Rt = 6.44 min (M + H)⁺ = 591(36%), Rt = 7.29 min (M + H)⁺ = 619(64%) 340 Rt = 5.67 (M + H)⁺ = 615(18%), Rt = 6.46 min (M + H)⁺ = 643 (79%) 341 Rt = 6.51 min (M + H)⁺ =591 (8%) 342 Rt = 5.37 min (M + H)⁺ = 549 (25%), Rt = 6.20 min (M + H)⁺= 577 (75%) 343 Rt = 6.54 min (M + H)⁺ = 627 (19%), Rt = 7.40 min (M +H)⁺ = 655 (81%) 344 Rt = 6.64 min (M + H)⁺ = 641 (30%), Rt = 7.52 min(M + H)⁺ = 669 (69%) 345 Rt = 6.41 min (M + H)⁺ = 611 (58%), Rt = 7.26min (M + H)⁺ = 639 (42%)

Example 20

(20-a) General Method 12, (20-b) General Method 19, (20-c) GeneralMethod 6, (20-d) General Method 20, (20-e) General Method 21, (20-f)General Method 9 for adenosine containing compounds only, then GeneralMethod 3b for all compounds.

Analysis of Some Typical Example Compounds:

proton NMR (400 MHz, d₆-DMSO): δ: 8.37 (s, 1H); 8.24 (s, 1H); 7.57 (d,2H, J=8.8 Hz); 7.35 (d, 2H, J=7.2 Hz); 7.30 (t, 2H, J=7.6 Hz); 7.21 (t,2H, J=7.2 Hz), 6.77 (d, 2H, J=8.8 Hz), 5.81 (d, 1H, J=4.4 Hz); 4.71-4.63(m, 3H), 4.64 (t, 1H, J=4.8 Hz); 4.46-4.38 (m, 2H); 4.33-4.30 (m, 1H),3.76 (s, 3H).

Beta Isomer:

proton NMR (400 MHz, d₆-DMSO): δ: 8.27 (s, 1H), 7.88 (s, 1H), 7.55-7.41(m, 6H); 7.28 (dd, 2H, J=1.2, 7.6 Hz); 6.84 (d, 2H, J=8.8 Hz); 5.31 (d,1H, J=2 Hz); 4.66 (d, 1H, J=11.2 Hz); 4.51 (s, 1H); 4.41-4.32 (m, 3H);3.97-3.88 (m, 3H); 2.98 (s, 3H); 1.73-1.66 (m, 2H); 1.39-1.26 (m, 12H);0.87-0.84 (m, 3H).

Alpha Isomer:

proton NMR (400 MHz, d₆-DMSO): δ: 8.25 (s, 1H), 7.82 (d, 3H, J=8.4 Hz);7.51-7.46 (m, 6H); 7.11 (d, 2H, J=8.8 Hz); 5.43 (d, 1H, J=4.4 Hz); 4.91(s, 1H); 4.37 (s, 1H); 4.23 (q, 1H, J=5.6, 8.8 Hz); 4.06 (t, 2H, J=6.4Hz); 3.79 (s, 3H); 1.77-1.70 (m, 2H); 1.44-1.26 (m, 12H); 0.87-0.84 (m,3H).

Example 21

(21-a) General Method 12, (21-b) General Method 6, (21-c) General Method7, (21-d) General Method 1 or 22, (21-e) General Method 9, (21-f)General Method 3-b then General Method 3a.

Analysis of Some Typical Example Compounds:

proton (400 MHz, d⁶-DMSO): 8.36 (s, 1H, H-8), 8.25 (s, 1H, H-2), 7.88(s, 2H, ArCH), 7.62 (d, 2H, J=8.8 Hz, ArCH), 6.84 (d, 2H, J=8.8 Hz,ArCH), 5.85 (d, 1H, J=3.6 Hz, H′-1), 4.73 (dd, 1H, J=3.5, 15.8 Hz, CH),4.57-4.64 (m, 2H, CH₂), 4.36 (t, 1H, J=5.6 Hz, CH), 4.22 (m, 1H, H′-4),3.80 (s, 3H, OCH₃).

Example 22

(22-a) General Method 1, general method 4 (22-13) General Method 12,(22-c) General Method 23, (22-d) General Method 9, (22-e) General Method3-a.

Analysis of Some Typical Example Compounds:

Isomer1:

proton NMR (400 MHz, d₆-DMSO): δ: 8.48 (s, 1H); 8.17 (s, 1H); 7.39-7.22(m, 6H); 7.11 (d, 2H, J=7.6 Hz); 6.86 (d, 2H, J=6.8 Hz); 5.93 (d, 1H,J=4.8 Hz); 4.67 (t, 1H, J=4.8 Hz); 4.59 (t, 1H, J=3.6 Hz); 4.34 (t, 1H,J=5.2 Hz); 4.22 (q, 1H, J=4.8, 10 Hz); 4.00 (dd, 1H, J=6.8, 15.2 Hz);3.76 (dd, 1H, J=7.6, 14.8 Hz); 3.26 (dd, 1H, J=4.4, 14 Hz); 3.05 (dd,1H, J=3.6, 14.4 Hz).

Isomer2:

proton NMR (400 MHz, d₆-DMSO): δ: 8.59 (s, 1H); 8.31 (s, 1H); 7.38-7.23(m, 5H); 7.11-7.06 (m, 3H); 6.88 (d, 2H, J=6.8 Hz); 5.97 (d, 1H, J=6Hz); 4.84 (t, 1H, J=4.8 Hz); 4.50 (t, 1H, J=3.6 Hz); 4.25-4.22 (m, 2H);4.14 (dd, 1H, J=3.6, 14.8 Hz); 3.23 (dd, 1H, J=5.2, 14.4 Hz); 3.00 (dd,1H, J=2.8, 14 Hz).

Isomer 1:

proton NMR (400 MHz, d₆-DMSO): δ: 10.94 (s, 1H); 8.59 (s, 1H); 8.26 (s,1H); 7.48 (d, 1H, J=8 Hz); 7.32-7.26 (m, 4H); 7.10 (s, 1H); 7.06 (t, 1H,J=7.6 Hz); 6.93 (t, 1H, J=7.6 Hz); 6.69-6.67 (m, 2H); 5.95 (d, 1H, J=5.2Hz); 4.66 (t, 1H, J=5.6 Hz); 4.54 (t, 1H, J=3.2 Hz); 4.33 (t, 1H, J=4.8Hz); 4.25 (q, 1H, J=5.2, 10.8 Hz); 4.00 (dd, 1H, J=6.4, 15.2 Hz); 3.76(dd, 1H, J=4, 14.8 Hz); 3.37-3.25 (m, 2H).

Isomer 2:

proton NMR (400MHz, d₆-DMSO): δ: 10.95 (s, 1H); 8.68 (s, 1H); 7.43 (d,1H, J=8 Hz); 7.32 (d, 2H, J=8 Hz); 7.27-7.25 (m, 2H); 7.09 (s, 1H); 7.06(t, 1H, J=8 Hz); 6.92 (t, 1H, J=8 Hz); 6.70 (dd, 2H, J=3.6, 7.6 Hz);5.99 (d, 1H, J=5.6 Hz); 4.81 (t, 1H, J=5.2 Hz); 4.47 (t, 1H, J=3.2 Hz);4.29-4.22 (m, 2H); 4.12 (dd, 1H, J=4.4, 14.8 Hz); 3.68 (dd, 1H, J=8.4,14.8 Hz); 3.36 (dd, 1H, J=5.2, 15.2 Hz); 3.24 (dd, 1H, J=2.4, 15.2 Hz).

Isomer 1:

proton NMR (400 MHz, d₆-DMSO): δ: 8.96 (s, 1H); 8.49 (s, 1H); 8.03 (s,1H); 7.73 (d, 2H, J=10.8 Hz); 7.67 (d, 2H, J=7.2 Hz); 7.49 (t, 2H, J=7.6Hz); 7.40-7.35 (m, 2H); 7.34 (d, 2H, J=8.4 Hz); 5.95 (d, 1H, J=5.6 Hz);4.70 (t, 1H, J=5.2 Hz); 4.65 (t, 1H, J=4.4 Hz); 4.31 (t, 1H, J=4.8 Hz);4.27-4.23 (m, 1H); 3.95 (dd, 1H, J=7.6, 15.2 Hz); 3.77 (dd, 1H, J=4,14.8 Hz); 3.26-3.24 (m, 2H).

Isomer 2:

proton NMR (400 MHz, d₆-DMSO): δ: 8.97 (s, 1H); 8.51 (s, 1H); 7.82 (s,1H); 7.73 (d, 2H, J=8.8 Hz); 7.67 (d, 2H, J=7.2 Hz); 7.49 (t, 2H, J=7.2Hz); 7.40-7.35 (m, 2H); 7.25 (d, 2H, J=8.4 Hz); 5.95 (d, 1H, J=5.6 Hz);4.79 (t, 1H, J=4.8 Hz); 4.62 (t, 1H, J=5.6 Hz); 4.27-4.22 (m, 2H); 4.16(dd, 1H, J=4, 14.8 Hz); 3.33-3.21 (m, 2H).

Example 23

(23-a) General Method 1, (23-b) General Method 4, (23-c) General Method6, (23-d) General Method 10, (23-e) General Method 4 or General Method20, (23-f) General Method 12. (23-g) General Method 9. (23-h) GeneralMethod 3a.

(23-i) General Method 22, (23-j) General Method 3-a

(23-k) General Method 7, (23-l) General Method 17, followed by treatmentof the resins with a 1.43 Molar solution (˜10 equivalents) of piperazinein dry DMF at room temperature overnight. The resin was then drained,washed (2×DMF and 3×DCM) and then dried in vacuo, General Method 12;(23-m)

General Method 3-a. Analysis of a Typical Example Compounds:

proton (400 MHz: d₆ DMSO) 3.79 (s, 3H, OCH₃), 4.30 (bs, 2H, H2, H3),4.43 (bd, J 6.0 Hz, 3H, H4, NCH₂Ph), 4.65 (dd, J 15.6, 6.2 Hz, 1H, H5a),4.91 (d, J 14.8 Hz, 1H, H5b), 5.35 (s, 1H, H1), 6.64 (d, J 8.8 Hz, 2H,ArH), 6.98 (d, J 8.8 Hz, 2H, ArH), 7.19 (d, J 8.8 Hz, 2H, ArH),7.22-7.36 (m, 5H, ArH, NHa), 7.42-7.56 (m, 5H, ArH), 7.71 (t, J 7.6 Hz,2H, ArH), 7.82 (bs, 1H, NHb).

proton (400 MHz: d₆ DMSO) 4.24-4.31 (m, 1H, H4), 4.38 (dd, J 7.4, 5.0Hz, 1H, H3), 4.47 (dd, J 4.4, 1.6 Hz, 1H, H2), 4.50 (dd, J 15.6, 7.6 Hz,1H, H5a), 4.76 (dd, J 15.6, 2.8 Hz, 1H, H5b), 5.33 (d, J 1.2 Hz, 1H,H1), 7.29 (dd, J 7.8, 1.4 Hz, 2H, ArH), 7.40-7.62 (m, 8H, ArH, ArCONHa),7.68 (d, J 8.4 Hz, 2H, ArH), 7.83 (s, 1H, ArCONHb), 7.88 (d, J 8.8 Hz,2H, ArH), 7.91-7.99 (m, 3H, ArH), 10.46 (s, 1H, ArNHCOPh).

Example 24

(24-a) General Method 1, (24-b) General Method 4, (24-c) General Method12, (24-d) General Method 13, (24-e) General Method 3-b.

Analysis of Some Typical Example Compounds:

proton (d⁶-DMSO, 400 MHz): 8.51 (s, 1H, H-2/8), 8.31 (s, 1H, H-2/8),7.60-7.05 (m, 8H, ArCH), 5.86 (d, 1H, J=5.6, Hz, H′-1), 4.67 (t, 1H,J=5.5 Hz, H′-2/3), 4.64 (d, 1H, J_(AB)=16.1 Hz, HA-), 4.39 (d, 1H,J_(AB)=16.1 Hz, HB—), 4.34 (t, 1H, J=5.1 Hz, H-2/3), 4.09 (t, 1H, J=4.2Hz,), 3.99 (m, 1H, H′-4), 3.67 (dd, 1H, J=5.8 Hz, 14.0 Hz, HA), 3.58(dd, 1H, J=7.6, 14.0 Hz, HB), 3.14 (dd, 1H, J=5.1, 14.4 Hz, H′-5A), 3.02(dd, 1H, J=4.6, 14.4 Hz, H′-5B).

proton (d⁶-DMSO, 400 MHz): 8.48 (s, 1H, H-2/8), 8.29 (s, 1H, H-2/8),7.57-7.00 (m, 8H, ArCH), 5.88 (d, 1H, J=5.8 Hz, H′-1), 4.68 (t, J=5.2Hz, H′—), 4.60 (d, 1H, J_(AB)=16.1 Hz, H—), 4.38 (d, 1H, J_(AB)=16.1 Hz,H), 4.34 (t, 1H, J=5.1 Hz, H—), 4.07 (t, 1H, J=4.6 Hz, H), 4.01 (m, 1H,H′-4), 3.64 (d, 2H, AB system, H—), 3.12 (dd, 1H, J=5.2, 14.6 Hz,H_(A)—), 3.01 (dd, 1H, J=4.4, 14.6 Hz, H₈—).

Exemplary Compounds of the Invention:

The substructures A-H listed below are substituents in the field R1 inthe libraries of compounds that follow.

Others substituents referred to in the following libraries may besubsequently found in the text at the end of examples.

Example 25

R (on Comp. R1 R2 ISOMER arm) 1 A IIa-1 L and D H 2 A IIb-1 L and D H 3A IIc-1 L and D H 4 A IId-1 L and D H 5 A IIe-1 L H 6 A IIe-1 D H 7 AIIf-1 L and D H 8 A IIg-1 L and D H 9 A Ilh-1 L and D H 10 A IIi-1 L andD H 11 A IIj-1 L and D H 12 A IIk-1 L and D H 13 A IIl-1 L and D H 14 AIIo-1 L H 15 A IIo-1 D H 16 B IIa-1 L and D methyl 17 B IIb-1 L and Dmethyl 18 B IIc-1 L and D methyl 19 B IId-1 L and D methyl 20 B IIe-1 Land D H 21 B IIf-1 L and D H 22 B IIh-1 L and D methyl 23 B IIi-1 L andD ethyl 24 B IIj-1 L and D ethvl 25 B IIk-1 L and D methyl 26 B IIr-1 Land D methyl 27 B IIl-1 L and D methyl 28 B IIo-1 L and D methyl 29 BIIp-1 L and D methyl 30 B IIq-1 L and D methyl

Example 26

R (on Comp. R1 R2 Isomer arm) 31 C IIa-1 L and D H 32 C IIb-1 L and D H33 D IIb-1 L and D H 34 C IIc-1 L and D H 35 C IId-1 L and D H 36 DIId-1 L and D H 37 D IIe-1 L and D H 38 C IIe-1 L and D H 39 D IIf-1 Land D H 40 C IIf-1 L and D H 41 D IIg-1 L and D H 42 C IIh-1 L and D H43 D IIh-1 L and D H 44 C IIi-1 L H 45 D IIi-1 L H 46 C IIj-1 L H 47 DIIj-1 L H 48 C IIk-1 L and D H 49 D IIk-1 L and D H 50 C IIr-1 L H 51 DIIr-1 L H 52 C IIl-1 L H 53 D IIl-1 L H 54 C IIn-1 L H 55 D IIn-1 L H 56C IIo-1 L H 57 D IIo-1 L H 58 C IIp-1 L H 59 D IIp-1 L H 60 C IIq-1 L H61 D IIq-1 L H 62 C IIb-1 L H 63 D IIb-1 L H 64 C IIe-1 L H 65 D IIe-1 LH

Example 27

Comp. R1 R2 R3 R4 66 A α4 ν2 Σ1 67 A β7 ν2 Σ1 68 A β6 ν2 Σ1 69 A χ5 ν2Σ1 70 A κ4 ν2 Σ1 71 A α4 ν2 α4 72 A β7 ν2 α4 73 A β6 ν2 α4 74 A χ5 ν2 α475 A κ4 ν2 α4 76 A α4 α1 Σ1 77 A β7 α1 Σ1 78 A β6 α1 Σ1 79 A χ5 α1 Σ1 80A κ4 α1 Σ1 81 A α4 α1 α1 82 A β7 α1 α1 83 A β6 α1 α1 84 A χ5 α1 α1 85 Aκ4 α1 α1

Example 28

Comp. R1 R2 86 A β1 87 A γ1 88 A β2 89 A δ2 90 A ε1 91 A κ1 92 A π1 93 Aω1 94 A ε2 95 A σ1 96 A β3 97 A γ2 98 A γ3 99 A δ2 100 A ε3 101 A κ2 102A π2 103 A ε4 104 A β4 105 A γ4 106 A β5 107 A φ1 108 A π3 109 A φ2 110A ν1 111 A ν2 112 A ν3 113 A ν4 114 A λ1 115 A ν5 116 A ν6 117 A ε5 118A ε6 119 A ν7 120 A χ1

Example 29

Comp. R1 R2 121 C α1 122 C β1 123 C γ1 124 C β2 125 C δ1 126 C ε1 127 Cκ1 128 C π1 129 C ω1 130 C ε2 131 C σ1 132 C β3 133 C γ2 134 C γ3 135 Cδ2 137 C ε3 137 C κ2 138 C π2 139 C ε4 140 C β4 141 C γ4 142 C β5 143 Cφ1 144 C π3 145 C φ2 146 C ν1 147 C ν2 148 C ν3 149 C ν4 150 C λ1 151 Cν5 152 C ν6 153 C ρ1 154 C ε5 155 C ε6 156 C ρ2 157 C ν7 158 C χ1 159 Dα1 160 D β1 161 D γ1 162 D β2 163 D δ1 164 D ε1 165 D κ1 166 D π1 167 Dω1 168 D ε2 169 D σ1 170 D β3 171 D γ2 172 D γ3 173 D δ2 174 D ε3 175 Dκ2 176 D π2 177 D ε4 178 D β4 179 D γ4 180 D β5 181 D φ1 182 D π3 183 Dφ2 184 D ν1 185 D ν2 186 D ν3 187 D ν4 188 D λ1 189 D ν5 190 D ν6 191 Dρ1 192 D ε5 193 D ε6 194 D ρ2 195 D ν7 196 D χ1

Example 30

Comp. R1 R2 R3 197 A π4 ψ1 198 A β1 ψ1 199 A ξ1 ψ1 200 A ε5 ψ1 201 A ε2ψ1 202 A σ1 ψ1 203 A α2 ψ1 204 A μ1 ψ1 205 A τ1 ψ1 206 A τ2 ψ1 207 A μ2ψ1 208 A ε7 ψ1 209 A μ3 ψ1 210 A γ2 ψ1 211 A γ5 ψ1 212 A π4 α1 213 A β1α1 214 A ξ1 α1 215 A ε5 α1 216 A ε2 α1 217 A σ1 α1 218 A α2 α1 219 A μ1α1 220 A τ1 α1 221 A τ2 α1 222 A ε7 α1 223 A μ3 α1 224 A γ2 α1 225 A γ5α1 226 C π4 ψ1 227 C β1 ψ1 228 C ξ1 ψ1 229 C ε5 ψ1 230 C μ1 ψ1 231 C τ1ψ1 232 C τ2 ψ1 233 C μ2 ψ1 234 C ε7 ψ1 235 C μ3 ψ1 236 C γ2 ψ1 237 C γ5ψ1 238 C ξ1 α1 239 C ε5 α1 240 C ε2 α1 241 C σ1 α1 242 C α2 α1 243 C μ1α1 244 C τ1 α1 245 C τ2 α1 246 C μ2 α1 247 C ε7 α1 248 C μ3 α1 249 C γ2α1 250 C γ5 α1 251 D π4 α1 252 D β1 α1 253 D ε2 ψ1 254 D σ1 ψ1

Example 31

Comp. R1 R2 255 A σ2 256 A ξ3 257 A β6 258 A θ1 259 A ε8 260 A χ2 261 Aχ3 262 A χ4 253 A ν8 264 A β8 265 A π5 266 A μ4 267 A μ5 268 A τ3 269 Aα3 270 A τ4 271 A σ3 272 A β9 273 A μ6 274 C ξ2 275 C β6 276 C φ1 277 Cθ1 278 C χ2 279 C χ3 280 C χ4 281 C ν8 282 C β8 283 C π5 284 C μ4 285 Cμ5 286 C τ3 287 C α3 288 C τ4 289 C σ3 290 C β9 291 C μ6 292 D σ2 293 Dξ2 294 D β6 295 D φ1 296 D θ1 297 D ε8 298 D χ2 299 D χ3 300 D χ4 301 Dν8 302 D β8 303 D π5 304 D μ4 305 D μ5 306 D τ3 307 D α3 308 D τ4 309 Dσ3 310 D β9 311 D μ6

Example 32

Comp. R1 R2 R3 312 A Σ2 α4 313 A Σ2 β6 314 A Σ2 χ5 315 A Σ2 ε9 316 A Σ2β7 317 A Σ2 ε10 318 A ψ1 θ2 319 A Σ2 ε11 320 A Σ2 χ6 321 A ψ1 χ4 322 AΣ2 σ3 323 C Σ2 α4 324 C Σ2 β6 325 C Σ2 χ5 326 C Σ2 ε9 327 C ψ1 β7 328 Cψ1 ε10 329 C Σ2 θ2 330 C Σ2 ξ3 331 C Σ2 ε11 332 C Σ2 χ6 333 C Σ2 χ4 334C ψ1 σ3 335 D Σ2 α4 336 D Σ2 β6 337 D Σ2 χ5 338 D Σ2 ε9 339 D ψ1 β7 340D Σ2 ε10 341 D Σ2 θ2 342 D Σ2 ε11 343 D Σ2 χ6 344 D Σ2 χ4 345 D ψ1 σ3

Example 33

Comp. R1 R2 346 A χ5 347 D χ5 348 A ε9 349 D ε9 350 A χ6 351 D χ7 352 Aα1 353 C α1 354 D α1 355 A θ3 356 C θ3 357 D θ3 358 A γ3 359 C γ3 360 Dγ3 361 A θ4 362 C θ4 363 D θ4 364 A γ1 365 C γ1 366 D γ1 367 A ε3 368 Cε3 369 D ε3 370 A χ1 371 C χ1 372 D χ1 373 A ε5 374 C ε5 375 D ε5 376 Aκ1 377 C κ1 378 D κ1 379 A θ1 380 C θ1 381 D θ1 382 A κ2 383 C κ2 384 Dκ2 385 A α5 386 C α5 387 D α5 388 A β10 389 C β10 390 D β10 391 A γ6 392C γ6 393 D γ6 394 A ν2 395 C ν2 396 D ν2

Example 34

Comp. R1 R2 397 A θ1 398 C θ1 399 D θ1 400 A α4 401 A ε11 402 A χ8 403 Aε9 404 A ξ3 405 A ω2 406 A α6 407 A μ7 408 A φ3 409 A τ4 410 A α7 411 Aμ8 412 A α1 413 A ε10 414 A κ3 415 A ε12 416 A γ7 417 A γ8 418 A γ9 419C α4 420 C ε11 421 C χ8 422 C ε9 423 C ξ3 424 C ω2 425 C α6 426 C μ7 427C φ3 428 C τ4 429 C α7 430 C μ6 431 C α1 432 C ε10 433 C κ3 434 C ε12435 C γ7 436 C γ8 437 C γ9 438 D α4 439 D ε11 440 D χ8 441 D ε9 442 D ξ3443 D ω2 444 D α6 445 D μ7 446 D φ3 447 D τ4 448 D α7 449 D μ8 450 D α1451 D ε10 451 D κ3 453 D ε12 454 D γ7 455 D γ8 456 D γ9

Example 35

Comp. R1 R2 457 D θ1 458 D β8 459 D χ3 460 D μ6 461 D μ9

Example 36

Comp. R1 R2 462 D ε2 463 D σ1 464 D δ2 465 D β4 466 D φ1

Example 37

Compound No. R1 R2 R3 467 E χ3 Σ3 468 E μ6 Σ3 469 E χ2 Σ3 470 E χ3 ψ1471 E μ6 ψ1 472 E σ3 ψ1 473 E χ4 ψ1 474 E χ2 ψ1 475 C χ3 ψ1 476 C μ6 ψ1477 C σ3 ψ1 478 C χ4 ψ1 479 C χ2 ψ1 480 A χ3 ψ1 481 A μ6 ψ1 482 A σ3 ψ1483 A χ4 ψ1 484 A χ2 ψ1

Example 38

Compound No R1 R2 R3 485 A χ5 ψ1 486 A χ9 ψ1 487 A χ7 ψ1 488 A χ10 ψ1489 A χ11 ψ1 490 A χ12 ψ1 491 A χ13 ψ1 492 A χ14 ψ1 493 A χ15 ψ1 494 Aχ16 ψ1 495 A χ17 ψ1 496 A χ18 ψ1 497 A χ19 ψ1 498 A χ23 ψ1 499 A σ4 ψ1500 A χ20 ψ1 501 A ξ4 ψ1 502 A β11 ψ1 503 A χ21 ψ1 504 A χ22 ψ1 505 C χ5ψ1 506 C χ9 ψ1 507 C χ7 ψ1 508 C χ10 ψ1 509 C χ11 ψ1 510 C χ12 ψ1 511 Cχ13 ψ1 512 C χ14 ψ1 513 C χ15 ψ1 514 C χ16 ψ1 515 C χ17 ψ1 516 C χ18 ψ1517 C χ19 ψ1 518 C χ23 ψ1 519 C σ4 ψ1 520 C χ20 ψ1 521 C ξ4 ψ1 522 C β11ψ1 523 C χ21 ψ1 524 C χ22 ψ1 525 D χ5 ψ1 526 D χ9 ψ1 527 D χ7 ψ1 528 Dχ10 ψ1 529 D χ11 ψ1 530 D χ12 ψ1 531 D χ13 ψ1 532 D χ14 ψ1 533 D χ15 ψ1534 D χ16 ψ1 535 D χ17 ψ1 536 D χ18 ψ1 537 D χ19 ψ1 538 D χ23 ψ1 539 Dσ4 ψ1 540 D χ20 ψ1 541 D ξ4 ψ1 542 D β11 ψ1 543 D χ21 ψ1 544 D χ22 ψ1545 A χ5 χ1 546 A χ9 χ9-1 547 A χ7 χ7-1 548 A χ10 χ10-1 549 A χ11 χ11-1550 A χ12 χ12-1 551 A χ13 χ13-1 552 A χ14 χ14-1 553 A χ15 χ15-1 554 Aχ16 χ16-1 555 A χ17 χ17-1 556 A χ18 χ18-1 557 A χ19 χ19-1 558 A χ23χ23-1 559 A σ4 σ4-1 560 A χ20 χ20-1 561 A ξ4 ξ4-1 562 A β11 β4 563 A χ22χ22-1 564 C χ5 χ1 565 C χ9 χ9-1 566 C χ7 χ7-1 567 C χ10 χ10-1 568 C χ11χ11-1 569 C χ12 χ12-1 570 C χ13 χ13-1 571 C χ14 χ14-1 572 C χ15 χ15-1573 C χ16 χ16-1 574 C χ17 χ17-1 575 C χ18 χ18-1 576 C χ19 χ19-1 577 Cχ23 χ23-1 578 C σ4 σ4-1 579 C χ20 χ20-1 580 C ξ4 ξ4-1 581 C β11 β4 582 Cχ22 χ22-1 583 D χ5 χ1 584 D χ9 χ9-1 585 D χ7 χ7-1 586 D χ10 χ10-1 587 Dχ11 χ11-1 588 D χ12 χ12-1 589 D χ13 χ13-1 590 D χ14 χ14-1 591 D χ15χ15-1 592 D χ16 χ16-1 593 D χ17 χ17-1 594 D χ18 χ18-1 595 D χ19 χ19-1596 D χ23 χ23-1 597 D σ4 σ4-1 598 D ξ4 ξ4-1 599 D β11 β4 600 D χ22 χ22-1

Example 39

Compound No R1 R2 R3 601 A ξ1 α1 602 A ε5 α1 603 A ε2 α1 604 A τ1 α1 605A τ2 α1 606 A μ3 α1 607 E τ2 α1 608 E μ2 α1 609 E μ3 α1 610 E γ5 α1

Example 40

Compound No R1 R2 R3 R4 R5 611 C χ4 ψ1 ψ1 612 F χ5 ψ1 ψ1 613 D χ5 ψ1 ψ1614 C χ5 ψ1 ψ1 615 G χ5 ψ1 ψ1 616 H χ5 ψ1 ψ1 617 F χ5 κ5 ψ1 618 D χ5 κ5ψ1 619 C χ5 κ5 ψ1 620 G χ5 κ5 ψ1 621 H χ5 κ5 ψ1 622 F χ5 ψ1 ν5 623 D χ5ψ1 ν5 624 C χ5 ψ1 ν5 625 G χ5 ψ1 ν5 626 H χ5 ψ1 ν5 627 F χ5 β12 β12 628D χ5 β12 β12 629 C χ5 β12 β12 630 G χ5 β12 β12 631 H χ5 β12 β12 632 Fχ18 ψ1 ψ1 633 D χ18 ψ1 ψ1 634 C χ18 ψ1 ψ1 635 G χ18 ψ1 ψ1 636 H χ18 ψ1ψ1 637 F χ18 κ5 ψ1 638 D χ18 κ5 ψ1 639 C χ18 κ5 ψ1 640 G χ18 κ5 ψ1 641 Hχ18 κ5 ψ1 642 F χ18 ψ1 ν5 643 D χ18 ψ1 ν5 644 C χ18 ψ1 ν5 645 G χ18 ψ1ν5 646 H χ18 ψ1 ν5 647 F χ18 β12 β12 648 D χ18 β12 β12 649 C χ18 β12 β12650 G χ18 β12 β12 651 H χ18 β12 β12 652 F χ4 ψ1 ψ1 653 D χ4 ψ1 ψ1 654 Gχ4 ψ1 ψ1 655 H χ4 ψ1 ψ1 656 F χ4 κ5 ψ1 657 D χ4 κ5 ψ1 658 C χ4 κ5 ψ1 659G χ4 κ5 ψ1 660 H χ4 κ5 ψ1 661 F χ4 ψ1 ν5 662 D χ4 ψ1 ν5 663 C χ4 ψ1 ν5664 G χ4 ψ1 ν5 665 H χ4 ψ1 ν5 666 F χ4 β12 β12 667 D χ4 β12 β12 668 C χ4β12 β12 669 G χ4 β12 β12 670 H χ4 β12 β12 671 F χ5 χ1 ψ1 ψ1 672 D χ5 χ1ψ1 ψ1 673 C χ5 χ1 ψ1 ψ1 674 G χ5 χ1 ψ1 ψ1 675 H χ5 χ1 ψ1 ψ1 676 F χ5 χ1κ5 ψ1 677 D χ5 χ1 κ5 ψ1 678 C χ5 χ1 κ5 ψ1 679 G χ5 χ1 κ5 ψ1 680 H χ5 χ1κ5 ψ1 681 F χ5 χ1 ψ1 ν5 682 D χ5 χ1 ψ1 ν5 683 C χ5 χ1 ψ1 ν5 684 G χ5 χ1ψ1 ν5 685 H χ5 χ1 ψ1 ν5 686 D χ5 χ1 β12 β12 687 C χ5 χ1 β12 β12 688 G χ5χ1 β12 β12 689 H χ5 χ1 β12 β12 690 F χ18 χ18-1 ψ1 ψ1 691 C χ18 χ18-1 ψ1ψ1 692 G χ18 χ18-1 ψ1 ψ1 693 H χ18 χ18-1 ψ1 ψ1 694 H χ18 χ18-1 κ5 ψ1 695F χ18 χ18-1 ψ1 ν5 696 C χ18 χ18-1 ψ1 ν5 697 D χ18 χ18-1 ψ1 ν5 698 G χ18χ18-1 ψ1 ν5 699 H χ18 χ18-1 ψ1 ν5 700 F χ18 χ18-1 β12 β12 701 D χ18χ18-1 β12 β12 702 C χ18 χ18-1 β12 β12 703 G χ18 χ18-1 β12 β12 704 H χ18χ18-1 β12 β12 705 F χ4 χ24 ψ1 ψ1 706 C χ4 χ24 ψ1 ψ1 707 G χ4 χ24 ψ1 ψ1708 H χ4 χ24 ψ1 ψ1 709 F χ4 χ24 κ5 ψ1 710 D χ4 χ24 κ5 ψ1 711 C χ4 χ24 κ5ψ1 712 H χ4 χ24 κ5 ψ1 713 D χ4 χ24 ψ1 ν5 714 F χ4 χ24 β12 β12

Example 41

Compound No. R1 R2 R3 715 A χ5 α1 716 C χ5 α1 717 A χ3 α1 718 C χ3 α1719 A σ3 α1 720 C σ3 α1 721 A χ5 ν5 722 C χ5 ν5 723 C χ5 ν5 724 A χ3 ν5725 C χ3 ν5 726 C χ3 ν5 727 A σ3 ν5 728 C σ3 ν5 729 C σ3 ν5

Example 42

Compound No R1 R2 R3 730 A β2 α1 731 A ε5 α1 732 A β3 α1 733 A χ19 α1734 A χ1 α1 735 A γ10 α1 736 A ξ5 α1 737 A σ1 α1 738 A χ4-1 α1 739 A μ10α1 740 A φ2 α1 741 A α4 α1 742 A α8 α1 743 A β2 β2 744 A ε5 β2 745 A β3β2 746 A χ19 β2 747 A χ1 β2 748 A γ10 β2 749 A ξ5 β2 750 A σ1 β2 751 Aχ4-1 β2 752 A μ10 β2 753 A φ2 β2 754 A α4 β2 755 A α8 β2 756 A β2 ε5 757A ε5 ε5 758 A β3 ε5 759 A χ19 ε5 760 A χ1 ε5 761 A γ10 ε5 762 A ξ5 ε5763 A σ1 ε5 764 A χ4-1 ε5 765 A μ10 ε5 766 A φ2 ε5 767 A α4 ε5 768 A α8ε5 769 A β2 ξ1 770 A ε5 ξ1 771 A β3 ξ1 772 A χ1 ξ1 773 A γ10 ξ1 774 A σ1ξ1 775 A χ4-1 ξ1 776 A μ10 ξ1 777 A φ2 ξ1 778 A α4 ξ1 779 A α8 ξ1 780 Aβ2 ψ1 781 A β2 ξ5 782 A ε5 ψ1 783 A ε5 ξ5 784 A β3 ψ1 785 A β3 ξ5 786 Aχ1 ψ1 787 A χ1 ξ5 788 A γ10 ψ1 789 A γ10 ξ5 790 A ξ5 ψ1 791 A ξ5 ξ5 792A σ1 ψ1 793 A σ1 ξ5 794 A χ4-1 ψ1 795 A μ10 ψ1 796 A μ10 ξ5 797 A φ2 ψ1798 A φ2 ξ5 799 A α8 ξ5 800 A α8 ξ5 801 A β2 ω1 802 A ε5 ω1 803 A β3 ω1804 A χ19 ω1 805 A χ1 ω1 806 A χ19 ψ1 807 A χ19 ξ5 808 A φ2 ω1 809 A μ10γ1 810 A φ2 γ1 811 A α4 γ1 812 A α8 γ1 813 A β2 κ2 814 A ε5 κ2 815 A β3κ2 816 A χ19 κ2 817 A χ1 κ2 818 A γ10 κ2 819 A χ5 κ2 820 A σ1 κ2 821 Aχ4-1 κ2 822 A μ10 κ2 823 A φ2 κ2 824 A α4 κ2 825 A α8 κ2 826 A β2 τ2 827A ε5 τ2 828 A β3 τ2 829 A χ19 τ2 830 A χ1 τ2 831 A γ10 τ2 832 A χ5 τ2833 A σ1 τ2 834 A χ4-1 τ2 835 A μ10 τ2 836 A φ2 τ2 837 A α4 τ2 838 A α8τ2 839 A β2 τ2 840 A ε5 μ2 841 A β3 μ2 842 A χ19 μ2 843 A χ1 μ2 844 Aγ10 μ2 845 A χ5 μ2 846 A μ2 μ2 847 A χ4-1 μ2 848 A μ10 μ2 849 A φ2 μ2850 A α4 μ2 851 A α8 μ2 852 A β2 χ1 853 A ε5 χ1 854 A β3 χ1 855 A χ19 χ1856 A χ1 χ1 857 A γ10 χ1 858 A χ5 χ1 859 A σ1 χ1 860 A ξ4-1 χ1 861 A φ2χ1 862 A α4 χ1 863 A α8 χ1 864 A β2 Σ4 865 A ε5 Σ4 866 A β3 Σ4 867 A χ19Σ4 868 A χ1 Σ4 869 A γ10 Σ4 870 A χ5 Σ4 871 A σ1 Σ4 872 A χ4-1 Σ4 873 Aμ10 Σ4 874 A φ2 Σ4 875 A α4 Σ4 876 A α8 Σ4 877 A α1 ν1 878 A α1 ν2 879 Aα1 ν9 880 A ν4 α1 881 A ν4 γ2 882 A ν4 τ2 883 A ν4 τ1 884 A χ1 ν4 885 Aμ7-1 α1 886 A μ7-1 γ2 887 A μ7-1 τ2 888 A μ7-1 τ1 889 A μ7-1 χ1 890 Aγ10 ε1 891 A χ5 ω1 892 A σ1 ω1 893 A χ4-1 ω1 894 A μ10 ω1 895 A α4 ω1896 A α8 ω1 897 A β2 γ1 898 A ε5 γ1 899 A β3 γ1 900 A χ19 γ1 901 A χ1 γ1902 A γ10 γ1 903 A ξ5 γ1 904 A σ1 γ1 905 A χ4-1 γ1 906 A μ11 χ1 907 Aμ11 τ2 908 A ν4 μ3 909 A α1 σ1 910 A σ1 β2 911 A σ1 ε5

Example 43

Compound No R1 R2 R3 R4 912 A χ4 ψ1 ψ1 913 A χ5 ψ1 ψ1 914 A χ18 ψ1 ψ1915 A χ5 ψ1 ν5 916 A χ18 ψ1 ν5 917 A χ5 κ5 ψ1 918 A χ4 κ5 ψ1 919 A χ18κ5 ψ1 920 A χ5 β12 β12 921 A χ4 β12 β12 922 A χ18 β12 β12

Example 44

Compound No R1 R2 R3 923 A α1 α4 924 A α1 β6 925 A α1 ε9 926 A α1 κ6 927A α1 σ3 928 A α1 χ8 929 A ψ1 α4 930 A ψ1 β6 931 A ψ1 ε9 932 A ψ1 κ6 933A ψ1 σ3 934 A ψ1 χ8 935 A μ7-1 α4 936 A μ7-1 β6 937 A μ7-1 ε9 938 A μ7-1κ6 939 A μ7-1 σ3 940 A μ7-1 χ8 941 A μ13 α4 942 A μ13 β6 943 A μ13 ε9944 A μ13 κ6 945 A μ13 σ3 946 A μ13 χ8 947 A α1 α4 948 A α1 β6 949 Aμ7-1 α4 950 A μ7-1 β6 951 A μ7-1 σ3 952 A μ13 σ3 953 A μ13 χ8

Example 45

Compound No R1 R2 R3 954 A β4 α1 955 A β2 α1 956 A ε3 α1 957 A γ2 α1 958A γ1 α1 959 A β3 α1 960 A β4 α1 961 A β2 α1 962 A ε3 α1 963 A γ2 α1 964A γ1 α1 965 A β3 α1

Example 46

Compound No R1 R2 R3 R4 966 C α1 ψ1 ψ1 967 G α1 ψ1 ψ1 968 H α1 ψ1 ψ1 969C α1 κ5 ψ1 970 G α1 κ5 ψ1 971 H α1 κ5 ψ1 972 C α1 ψ1 ν5 973 G α1 ψ1 ν5974 H α1 ψ1 ν5 975 C α1 β12 β12 976 G α1 β12 β12 977 h α1 β12 β12

Example 47

Compound No. R1 R2 R3 978 A σ2 σ2-1 979 A ξ2 ξ2-1 980 A β6 β2 981 A θ1θ3 982 A ε8 ε1 983 A β8 β3 984 A π5 π1 985 A τ3 τ1 986 A α3 α3-1 987 Aτ4 τ2 988 A σ3 σ1 989 C χ2 χ2-1 990 C χ3 ξ3-1 991 C χ4 χ4-1 992 C ν8 ν1993 C μ5 μ5-1 994 C τ3 τ1 995 C τ4 τ2 996 C μ6 μ6-1 997 D σ2 σ2-1 998 Dξ2 ξ2-1 999 D β6 β2 1000 D φ1 φ1-1 1001 D χ4 χ4-1 (χ24) 1002 D ν8 ν11003 D τ4 τ2 1004 D σ3 σ1 1005 D β9 β9-1 1006 D μ6 μ6-1 1007 A χ2 χ2-1

Example 48

Compound No. R1 R2 R3 1008 A α4 α1 1009 A ε11 ε3 1010 A χ8 χ8-1 1011 Aε9 ε5 1012 A ε2 ε1 1013 A α6 α6-1 1014 A φ3 φ2 1015 A τ4 τ5 1016 A α7α7-1 1017 A α1 α5 1018 A ε10 ε2 1019 A κ3 κ7 1020 A ε12 ε7 1021 A γ7 γ41022 A γ8 γ8-1 1023 A γ9 γ5 1024 C α4 α1 1025 C θ1 θ3 1026 C ε11 ε3 1027C χ8 χ8-1 1028 C ε9 ε5 1029 C ε3 ε1 1030 C α6 α6-1 1031 C φ3 φ2 1032 Cτ4 τ5 1033 C α7 α7-1 1034 C α1 α5 1035 C ε10 ε2 1036 C κ3 κ7 1037 C ε12ε7 1038 C γ7 γ4 1039 C γ8 γ8-1 1040 C γ9 γ5 1041 D α4 α1 1042 D θ1 θ31043 D ε11 ε3 1044 D χ8 χ8-1 1045 D ε9 ε5 1046 D ε2 ε1 1047 D α6 α6-11048 D φ3 φ2 1049 D α7 α7-1 1050 D ε10 ε2 1051 D κ3 κ7 1052 D ε12 ε71053 D γ7 γ4 1054 D γ8 γ8-1 1055 D γ9 γ5

Example 49 Selected Activity Data Tested at 25 Micromolar Except !Tested at 2.5 micromolar

compound number EGF-R c-Kit VEGF ABL MET PDGFalpha CDK2 Tie2 PKC P38 10069 52 58 109 88 106 70 42 80 146 94 53 101 115 78 127 270 71 142 212 2312 10 41 46 38 25 1 26 223 22 109 11 24 31 17 40 0 10 246 15 6 8 30 2728 26 −1 13 279 66 17 31 6 72 85 20 12 80 345 58 40 54 74 87 82 67 41 65456 96 92 96 107 103 113 28 91 104 466 84 55 72 110 102 104 114 88 87486

24 45 96 100 488

34 136 82 100 508

12 17 16 100 528

12 44 26 101 604 27 13 18 49 46 46 30 3 50 100 605 20 18 14 55 54 56 265 27 100 658

20 55 5 99 659

17 63 8 94 668

16 1 669

11 34 1 97 670

9 23 1 718

7 8 1 725

6 10 912 88 38 44 96 88 96 119 72 96 70 Blank = not determined. Thefollowing lists examples of compound numbers that demonstrate activityEGF-R inhibitors at 25 micromolar: 470, 471, 472, 478, 480, 604, 605,611, 100, 198, 205, 207, 209, 212, 213, 214, 215, 216, 218, 211, 220,221, 222, 223, 224, 225, 227, 233, 235, 238, 240, 241, 246, 248, 254,273, 279, 291, 334, 345, 350, 386, 391, 392, 393: c-Kit inhibitors at 25micromolar: 470, 471, 472, 473, 474, 480, 482, 483, 484, 604, 605, 611,912, 486, 488, 501, 504, 508, 528, 606, 607, 608, 609, 610, 654, 657,658, 659, 660, 663, 664, 665, 666, 667, 668, 669, 670, 99, 100, 103,104, 108, 109, 110, 122, 125, 127, 130, 131, 132, 133, 135, 136, 137,138, 139, 140, 143, 144, 145, 146, 148, 154, 155, 163, 168, 169, 170,173, 174, 175, 177, 178, 180, 181, 183, 184, 186, 192, 193, 198, 204,205, 207, 209, 212, 213, 214, 217, 218, 211, 220, 221, 222, 225, 227,233, 235, 238, 240, 241, 246, 248, 254,: 228, 242, 244, 245, 247, 250,252, 253, 260, 261, 262, 271, 264, 273, 279, 282, 286, 289, 291, 299,309, 321, 322, 332, 333, 334, 345, 346, 362, 370, 377, 378, 379, 386,398, 403, 404, 408, 427, 458, 459, 460, 462, 463, 464, 465, 466: VEGF-R2inhibitors at 25 micromolar: 472, 478,, 480, 482, 483, 484, 604, 605,611, 912, 486, 505, 508, 528, 604, 605, 606, 608, 658, 659, 660, 667,668, 669, 670, 100, 198, 205, 207, 209, 211, 212, 214, 215, 216, 218,220, 221, 222, 223, 224, 225, 227, 233, 235, 238, 244, 246, 252, 254,256, 271, 273, 279, 291, 345, 370, 371, 379, 403, 466: ABL inhibitors at25 micromolar: 470, 478, 480, 604, 605, 611, 107, 127, 135, 152, 156,157, 158, 159, 191, 207, 212, 214, 215, 220, 221, 223, 224, 225, 233,246, 273, 279, 291, 299, 330, 334, 345, 397: MET inhibitors at 25micromolar: 470, 480, 604, 605, 207, 212, 214, 217, 220, 221, 223, 224,225, 233, 238, 246, 279, 291: PDGF-Ralpha inhibitors at 25 micromolar:470, 604, 605, 207, 212, 214, 215, 220, 221, 223, 224, 225, 233, 246,202, 271, 321, 334, 370: CDK2 inhibitors at 25 micromolar: 470, 472,478, 604, 605, 611, 32, 100, 205, 207, 209, 212, 213, 214, 215, 216,218, 219, 220, 221, 222, 223, 224, 225, 233, 246, 273, 279, 291, 334,345, 456: Tie2 inhibitors at 25 micromolar: 470, 471, 472, 474, 478,480, 604, 605, 611, 912, 508, 528, 534, 535, 604, 605, 606, 607, 608,609, 610, 654, 657, 658, 659, 660, 667, 668, 669, 670, 71, 91, 92, 99,100, 101, 103, 104, 106, 107, 108, 109, 113, 114, 127, 131, 135, 136,138, 139, 143, 144, 145, 146, 151, 152, 153/154, 155, 160, 168, 177,178, 183, 192, 198, 205, 207, 209, 211, 212, 217, 214, 215, 216, 218,220, 221, 222, 223, 224, 225, 227, 231, 233, 235, 238, 240, 241, 244,246, 248, 250, 252, 254, 256, 271, 273, 279, 291, 333, 334, 345, 376,379, 446, 457, 459: PK-C inhibitors at 25 micromolar: 470, 471, 472,474, 478, 480, 604, 605, 611, 2, 205, 207, 209, 212, 213, 214, 215, 216,218, 219, 220, 221, 222, 223, 224, 225, 233, 246, 299, 321, 333, 334,345, 379: FGF-R1 inhibitors at 25 micromolar: 604, 605, 611, 100, 104,198, 205, 207, 211, 212, 214, 215, 216, 217, 218, 220, 221, 222, 223,224, 225, 227, 233, 238, 246, 248, 254, 273, 279, 291, 345:

indicates data missing or illegible when filed

Tables of Substituents:

α1

β1

γ1

β2

δ1

ε1

κ1

π1

ω1

ε2

σ1

β3

γ2

γ3

δ2

ε3

κ2

π2

ε4

β4

γ4

β5

φ1

π3

φ2

ν1

ν2

ν3

ρ1

ν4

λ1

ν5

ν6

ε5

ε6

ρ2

ν7

χ1

κ4

Σ1

π4

ξ1

α2

μ1

τ1

τ2

μ2

ε7

μ3

ψ1

γ5

σ2

ξ2

β6

θ1

ε8

χ2

χ3

χ4

ν8

β7

β8

π5

μ4

μ5

τ3

α3

τ4

μ10

κ6

β12

κ6

σ3

β9

μ6

ξ2

φ1

ξ3

Σ2

χ5

ε9

α4

ε10

θ2

ε11

χ6

χ7

θ3

θ4

α5

β10

γ6

χ8

ω2

α6

μ7

φ3

α7

τ4

μ8

κ3

ε12

γ7

γ8

γ9

μ9

χ9-1

χ10-1

χ11-1

χ12-1

χ13-1

χ14-1

χ15-1

χ16-1

χ17-1

χ18-1

χ19-1

χ20-1

χ21-1

χ22-1

χ23-1

β11

χ24 (χ4-1)

σ4-1

ξ4-1

χ7-1

μ11

χ9-1

χ10-1

χ11-1

χ12-1

χ13-1

χ14-1

χ15-1

χ16-1

χ17-1

χ18-1

χ19-1

χ20-1

χ21-1

χ22-1

χ23-1

β11

χ24 (χ4-1)

σ4-1

ξ4-1

χ7-1

μ11

σ2-1

ξ2-1

α3-1

χ2-1

χ3-1

μ5-1

μ6-1

χ8-1

φ1-1

β9-1

α6-1

τ5

α7-1

κ7

γ8-1, γ10

μ13

μ12

Throughout the specification and the claims (if present), unless thecontext requires otherwise, the term “comprise”, or variations such as“comprises” or “comprising”, will be understood to apply the inclusionof the stated integer or group of integers but not the exclusion of anyother integer or group of integers.

It should be appreciated that various other changes and modificationscan be made to any embodiment described without departing from thespirit and scope of the invention

1-66. (canceled)
 67. A method of identifying a compound that inhibits orenhances the activity of a protein kinase comprising: a) contacting saidprotein kinase with a compound of formula I, being a derivative of afuranose or pyranose form of a monosaccharide, or a pharmaceuticallyacceptable salt thereof

Wherein; n is 1 or 2, X is selected from the group consisting of: OR1,an unsubstituted 5 or 6 membered heterocyclic moiety, a substituted 5 or6 membered heterocyclic moiety, an unsubstituted 9 or 10 memberedheterobicyclic moiety and a substituted 9 or 10 membered heterobicyclicmoiety, R1 is selected from the group consisting of: C1 to C7 alkyl, C1to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl,C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl,Y is selected from the group consisting of an unsubstituted 5 or 6membered heterocyclic moiety; a substituted 5 or 6 membered heterocyclicmoiety, an unsubstituted 9 or 10 membered heterobicyclic moiety and asubstituted 9 or 10 membered heterobicyclic moiety; an amino acid, adipeptide, and

R6 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 toC14 heteroaryl, C6 to C14 arylalkyl or C3 to C14 heteroarylalkyl, withthe proviso that R6, R7 and R8 are not all H, R9 is selected from H, or—(CO)—R6, R7, R8, R11, R12, R14, are independently selected from thegroup consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to C14arylalkyl and C6 to C14 heteroarylalkyl, R13 is selected from the groupconsisting of: unsubstituted phenyl unsubstituted benzyl, substitutedphenyl, substituted benzyl, H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 toC7 alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 toC14 arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to C14arylalkyl or C6 to C14 heteroarylalkyl, —S—R6 and —O—R6, R15 is absentor is at least one substituent on the aromatic ring which areindependently selected from the group consisting of: OH, NO, NO₂, NH₂,N₃, halogen, CF₃, CHF₂, CH₂F, nitrile, alkoxy, aryloxy, amidine,guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acidamide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl,aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted orunsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide,hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, alkyl,aminoaryl, aminoheteroaryl, thioalkyl, thioaryl and thioheteroaryl, andb) determining the activity of said protein kinase in the presence ofsaid compound of formula I and in the absence of said compound offormula I, wherein, when the activity of said protein kinase in thepresence of said compound of formula I is higher than the activity ofsaid protein kinase in the absence of said compound of formula I, saidcompound of formula I is an enhancer of the activity of said proteinkinase, and when the activity of said protein kinase in the presence ofsaid compound of formula I is lower than the activity of said proteinkinase in the absence of said compound of formula I, said compound offormula I is an inhibitor of the activity of said protein kinase. 68.The method of claim 67, wherein R1 is substituted, cyclic or acyclic,branched and/or linear.
 69. The method of claim 67, wherein R7 and R8combine to form a cyclic structure.
 70. The method of claim 67, whereinR6 and one of R7 or R8 combine to form a cyclic structure.
 71. Themethod of claim 67, wherein R11 and R12 combine to form a cyclicstructure,
 72. The method of claim 67, wherein X is selected from: OR1,

R1 and R3 are independently selected from the group consisting of: C1 toC7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14heteroarylalkyl, R4 is selected from the group consisting of: H, C1 toC7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14heteroarylalkyl, R5 is selected from the group consisting of: H, C1 toC7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl or C3 to C14heteroarylalkyl, C1 to C7 acyl, C6 to C14 arylacyl, and C3 to C14heteroarylacyl, R2 is selected from the group consisting of: —(C═O)—R3,—(C═O)—OR4, and —(C═O)—NH—R4, Y is selected from:


73. The method of claim 72, wherein at least one of R1 to R5 issubstituted, cyclic or acyclic, branched and/or linear.
 74. The methodof claim 72, wherein R7 and R8 combine to form a cyclic structure. 75.The method of claim 72, wherein R6 and one of R7 or R8 combine to form acyclic structure.
 76. The method of claim 72, wherein R11 and R12combine to form a cyclic structure.
 77. The method of claim 67 whereinat least one of R1-R14 is substituted and these substituents and thesubstituents on the substituted 5 or 6 membered heterocyclic moiety andthe substituted 9 or 10 membered heterobicyclic moiety are selected fromthe group consisting of: OH, NO, NO₂, NH₂, N₃, halogen, CF₃, CHF₂, CH₂F,nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid,carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl,heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl,aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate,sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate,hydroxamic acid, heteroaryloxy, alkyl, aminoaryl, aminoheteroaryl,thioalkyl, thioaryl or thioheteroaryl, which may optionally be furthersubstituted.
 78. The method of claim 67 wherein the group X is


79. The method of claim 67, wherein the group X is


80. The method of claim 67, wherein X is —OR1
 81. The method of claim 72wherein the group Y is


82. The method of claim 72 wherein Y is


83. The method of claim 72, wherein Y is


84. The method of claim 72, wherein Y is


85. The method of claim 72, wherein Y is


86. The method of claim 72, wherein Y is


87. The method of claim 72, wherein Y is


88. The method of claim 67 wherein the protein kinase is a serine orthreonine kinase.
 89. The method of claim 67 wherein the protein kinaseis a tyrosine kinase.
 90. The method of claim 67 wherein the proteinkinase is selected from the group consisting of one or more of theisoforms of: A protein kinase C; B Tie-2, also known as TEK, HPK-6,TIE-2, VMCM, VMCM1; C c-Kit, also known as SCFR, CD117, PBT; DVEGF-R2/KDR; also known as VEGFR2, VEGFR-2, VEGFR, Hs.KDR, Hs.12337,FLK1, FLK-1; E EGF-R, also known as ERBB1, ERBB, EGFRvIII; F Abl, alsoknown as c-ab1, c-ABL, JTK7, p150, ABL1; G MET, also known as HGFR,C-MET, RCCP2; H CDK2, also known as p34CDK2, p33CDK2, p33CDK2; I PDGF,also known as PDGFR1, PDGFR, PDGF-R-beta, JTK12, CD140B, PDGFRB; JFGFR-1, also known as N-SAM, LOC51033, FLT2, FLJ14326, CEK, C-FGR,BFGFR, H5, H4, H3, H2, FLG; and K P38 MAP Kinase, also known asp38alpha, p38ALPHA, SAPK2a, SAPK2A, PRKM15, PRKM14, Mxi2, MXI2, Exip,EXIP, CSPB1, CSBP2, CSBP1, p38, RK, P38, MAPK14.